Purinone derivatives as hm74a agonists

ABSTRACT

The present invention relates to purinone derivatives which are agonists of the HM74a receptor. Further provided are compositions and methods of using the compounds herein, and their pharmaceutically acceptable salts for the treatment of disease.

This application claims benefit of priority to U.S. provisional patentapplication Ser. No. 60/815,955 filed Jun. 23, 2006, and to U.S.provisional patent application Ser. No. 60/922,818 filed on Apr. 11,2007, each of which is hereby incorporated in its entirety.

FIELD OF THE INVENTION

The present invention relates to agonists of the HM74a receptor,compositions thereof and methods of using the same.

BACKGROUND OF THE INVENTION

Coronary artery disease (or CAD) is the number one cause of death in theUnited States (Nature Med 2002, 8:1209-1262). The initiation andprogression of CAD involves a complex interplay between multiplephysiological processes, including inflammation, lipid homeostasis, andinsulin resistance/diabetes mellitus. Multiple clinical studies have nowshown that the three primary components of plasma lipids, low-densitylipoprotein (or LDL), high-density lipoproteins (or HDL), andtriglycerides (or TGs), are causally associated with the propensity todevelop atherosclerosis and CAD. Along side other risk factors such aspositive family history of CAD, elevated body-mass index, hypertension,and insulin resistance/diabetes mellitus, elevated plasma LDL and/orTG-rich lipoproteins and decreased plasma HDL levels have been definedas major cardiovascular risk factors by the National CholesterolEducation Program Adult Treatment Panel III (NCEP ATP III; Am J Cardio2003, 92: 19i-26i). Accordingly, therapeutic intervention strategiesdesigned to impact these plasma lipid components as well as those thatunderlie insulin resistance are of great interest to the medicalcommunity.

In terms of LDL-lowering, drugs of the statin class are structurallysimilar to the molecule hydroxymethylglutaryl-coenzyme A (HMG-CoA), abiosynthetic precursor of cholesterol. These drugs are competitiveinhibitors of the rate-limiting step of cholesterol biosynthesiscatalyzed by HMG-CoA reductase. Mechanistically, the statins lower LDLby upregulating the LDL receptor in the liver as well as by reducing therelease of LDL into the circulation. As a monotherapy, the statin classof lipid lowering agents can reduce plasma LDL concentrations by 30-60%and triglycerides by 25%, producing a reduction in the incidence of CADby 25-60% and the risk of death by 30%. Statins do not have anappreciable effect on HDL. A mechanistically distinct agent, Ezetimibe(Zetia, Merck and Co.), also possesses the ability to reduce plasma LDL,however it functions by inhibiting the absorption of cholesterol by thesmall intestine via antagonism of the NPC1L1 receptor (PNAS 2005, 102:8132-8137). Monotherapy with Ezetimibe typically lowers LDL by 20%,however when co-formulated with a statin, maximal reductions can exceed60%. As with the statins, however, Ezetimibe has a negligible effect onplasma HDL.

While statins can have a modest impact on circulating triglycerides,PPAR alpha agonists (or fibrates) are far superior in targeting thislipid endpoint. The fibrates function by increasing lipolysis andelimination of triglyceride-rich particles from plasma by activatinglipoprotein lipase and reducing production of apolipoprotein C-III (aninhibitor of lipoprotein lipase activity). One such fibrate, Fenofibrate(Tricor, Abott), has been shown in clinical studies to decrease plasmatriglyceride levels upwards of 40-60%. Interestingly, the fibrate classof lipid-lowering drugs also has a modest, but significant effect onboth LDL (20% reduction) and HDL (10% increase).

Currently, the statin class of LDL lowering agents remains thecornerstone of dyslipidemia therapy. Despite the substantial reductionin cardiovascular events that have been achieved with this therapeuticapproach, however, the cardio-protection that is afforded to patients bythese therapies is still incomplete. It is now clear that therapies thatare targeted to increase HDL cholesterol are critical in terms ofmaximizing patient cardio-protection. The only therapy available to datethat has the ability to effectively raise circulating levels ofcardio-protective HDL and consequently improve the progression ofatherosclerosis in CAD patients is nicotinic acid (niacin or vitaminB₃). Nicotinic acid was first reported to modify lipoprotein profiles in1955 (Altschul et al. Arch Biochem Biophys 1955, 54: 558-559). Itseffects are the most broad-spectrum of any available therapy,effectively raising HDL levels (20-30%) as well as lowering circulatingplasma LDL (16%) and triglycerides (38%). The clinical significance ofthis broad-spectrum activity has been revealed in multiple largeclinical studies. In the most recent ARBITER 2 (Arterial Biology for theInvestigation of the Treatment Effects of Reducing Cholesterol 2; Tayloret al. Circulation 2004, 110: 3512-3517) study, patients on statintherapy were randomized to either placebo or 1000 mg extended release(ER) niacin (Niaspan, Kos Pharmaceuticals). Patients receiving niacinexhibited a statistically significant decrease in carotid intima-mediathickness, a validated surrogate cardiovascular end point. This studyalso revealed a significantly reduced rate of intima-media thicknessprogression in subjects without detectable insulin resistance. Thisstudy indicates the incomplete cardio-protection that is offered bystatin therapy and substantiates the utility of nicotinic acid inreducing overall cardiac risk in low-HDL patients.

While nicotinic acid has been used clinically to modify lipid profilesfor over four decades, the mechanism of action of the compound hasremained largely obscure. It has long been known that acute nicotinicacid dosing results in a profound decrease in circulating free fattyacids (FFAs). This anti-lipolytic activity was first hypothesized in1980 to be mediated by a membrane receptor linked to a decrease inintracellular cAMP (cyclic AMP, or cyclic adenosine monophosphate, or3′-5′-cyclic adenosine monophosphate) levels (Aktories et al. FEBSLetters 1980, 115: 11-14). This hypothesis was later confirmed and theimplied G_(i/o) GPCR-coupling was verified using pertussis toxinsensitivity studies (Aktories et al. FEBS Letters 1983, 156: 88-92). Theidentification of specific nicotinic acid binding sites on the surfaceof adipose and spleen cells confirmed the membrane hypothesis andrefined, using modern-day techniques, the G-protein coupling of thereceptor itself (Lorenzen et al. Mol Pharm 2001, 59: 349-357). ThisG-protein mediated, anti-lipolytic activity of nicotinic acid was usedfor two decades to identify and characterize nicotinic acid analogues interms of their therapeutic potential. Finally, in 2003, two independentgroups simultaneously published the cloning of an orphan G_(i/o)-coupledGPCR, HM74a (Wise et al. J Biol Chem 2003, 278: 9869-9874; Tunaru et al.Nat Med 2003, 9: 352-355), which binds to nicotinic acid with highaffinity. As predicted, this receptor was shown to be expressed inadipose tissue and spleen, and binds to not only nicotinic acid, butalso to the structurally related derivatives that had been previouslyshown to exhibit adipocyte anti-lipolytic activity. Mice that have beenmade deficient in the rodent ortholog of HM74a (Puma-g) by homologousrecombination resist nicotinic acid-dependent FFA reduction and TGlowering. It is currently hypothesized that the nicotinic acidanti-lipolytic activity is based on the activation of this high affinityGPCR (HM74a), resulting in a decrease in intracellular cAMP and asubsequent attenuation of hormone sensitive lipase (HSL) activity.Decreased adipocyte lipolytic output results in a reduction incirculating FFA and a corresponding reduction in hepatic TGs, very-lowdensity LDL (VLDL), and LDL. The increased levels of HDL arise from aneffective reduction of cholesterol ester transfer protein activity dueto decreased availability of VLDL acceptor molecules.

Beyond impacting lipid levels and lipoprotein profiles, FFAs playfundamental roles in the regulation of glycemic control. It is nowrecognized that chronically elevated plasma FFA concentrations causeinsulin resistance in muscle and liver, and impair insulin secretion(reviewed in Defronzo et al. Int. J. Clin. Prac. 2004, 58: 9-21). Inmuscle, acute elevations in plasma FFA concentrations can increaseintramyocellular lipid content; this can have direct negative effects oninsulin receptor signaling and glucose transport. In liver, increasedplasma FFAs lead to accelerated lipid oxidation and acetyl-CoAaccumulation, the later of which stimulates the rate-limiting steps forhepatic glucose production. In the pancreas, long-term exposure toelevated FFAs has been shown to impair the beta-cell's ability tosecrete insulin in response to glucose. This data has driven thehypothesis that adipose tissue FFA release is a primary driver of theunderlying pathologies in type 2 diabetes, and strategies designed toreduce FFAs, for example by agonizing HM74A, may prove effective inimproving insulin sensitivity and lowering blood glucose levels inpatients with type 2 diabetics/metabolic syndrome

The utility of nicotinic acid as a hypolipidemic/FFA lowering agent iscurrently limited by four main factors. First, significant doses ofnicotinic acid are required to impact FFA release and improve lipidparameters Immediate release (IR) nicotinic acid is often dosed at 3-9g/day in order to achieve efficacy, and ER nicotinic acid (Niaspan) istypically dosed between 1-2 g/day. These high doses drive the secondissue with nicotinic acid therapy, hepatotoxicity. One of the mainmetabolic routes for nicotinic acid is the formation of nicotinamide(NAM). Increased levels of NAM have been associated with elevated livertransaminase which can lead to hepatic dysfunction. This toxicity isparticularly problematic for sustained release formulations and resultsin the need to monitor liver enzymes during the initiation of therapy.Third, high doses of nicotinic acid are associated with severeprostaglandin-mediated cutaneous flushing. Virtually all patientsexperience flushing when on IR-nicotinic acid at or near the T_(max) ofthe drug and discontinuation of therapy occurs in 20-50% of individuals.Niaspan, while exhibiting an increased dissolution time, still possessesa flushing frequency of approximately 70%, and this is in spite of therecommended dosing regimen that includes taking Niaspan along with anaspirin after a low-fat snack. Fourth, nicotinic acid therapy oftenresults in FFA rebound, a condition whereby free fatty acid levels arenot adequately suppressed throughout the dosing regimen, resulting in acompensatory increase in adipose tissue lipolysis. With immediaterelease nicotinic acid therapy, this rebound phenomenon is so great thatdaily FFA AUCs are actually increased after therapy. Such FFA excursionscan lead to impaired glycemic control and elevated blood glucose levels,both of which have been shown to occur in some individuals afternicotinic acid therapy.

Giving the importance of nicotinic acid in modulating (especiallyagonizing) HM74a receptor and its limitations, novel small moleculesdesigned to mimic the mechanism of nicotinic acid's action on HM74aoffer the possibility of achieving greater HDL, LDL, TG, and FFAefficacy while avoiding adverse effects such as hepatotoxicity andcutaneous flushing. Such therapies are envisioned to have significantimpact beyond dyslipidemia to include insulin resistance, hyperglycemia,and associated syndromes by virtue of their ability to more adequatelyreduce plasma FFA levels during the dosing interval. The presentinvention is directed to these, as well as other, important ends.

SUMMARY OF THE INVENTION

The present invention provides, inter alia, compounds of Formula I:

or pharmaceutically acceptable salts or prodrugs thereof, whereinconstituent members are defined herein.

The present invention further provides compositions comprising acompound of the invention and at least one pharmaceutically acceptablecarrier.

The present invention further provides methods of modulating HM74areceptor with a compound of the invention.

The present invention further provides methods of agonizing HM74areceptor by contacting the HM74a receptor with a compound of theinvention.

The present invention further provides methods of treating diseasesassociated with HM74a receptor.

The present invention further provides a compound of the invention foruse in therapy.

The present invention further provides a compound of the invention foruse in the preparation of a medicament for use in therapy.

DETAILED DESCRIPTION

The present invention provides, inter alia, compounds which are agonistsor partial agonists of HM74a and are useful in the treatment of avariety of diseases, such as cardiovascular diseases.

The compounds can have Formula I:

or pharmaceutically acceptable salt or prodrug thereof, wherein:

a dashed line indicates an optional bond;

X is N, CR^(3a), CR^(4a)R^(5a), or NR^(6a);

Y is N, CR^(3b), CR^(4b)R^(5b), or NR^(6b);

L is —(C₁₋₆ alkylene)-(Q¹)_(m)-(C₁₋₆ alkylene)_(p)-(Q²)_(q)-(C₁₋₆alkylene)_(r)-, optionally substituted with 1, 2, 3, 4, or 5 R^(L1),wherein if m and q are both 1, then p is 1;

R¹ is H, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, or Cy, wherein saidC₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, or C₂₋₁₀ alkynyl is optionally substitutedwith 1, 2, 3, 4, or 5 R^(L2);

R² is halo, cyano, C₁₋₃ haloalkyl, Z, SR^(A), or a moiety having theformula:

R^(3a) and R^(3b) are independently selected from H, halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, C₁₋₆cyanoalkyl, Cy¹, CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d),C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a), S(O)R^(b), S(O)NR^(c)R^(d),S(O)₂R^(b), NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d), wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl is optionally substituted with 1,2, or 3 substitutents independently selected from Cy¹, CN, NO₂, halo,OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d),NR^(c)C(O)OR^(a), S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b),NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d);

R^(4a), R^(4b), R^(5a), and R^(5b) are independently selected from H,halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆hydroxyalkyl, C₁₋₆ cyanoalkyl, Cy², CN, NO₂, OR^(a1), SR^(a1),C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1),OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)C(O)OR^(a1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), NR^(c1)S(O)₂R^(b1), andS(O)₂NR^(c1)R^(d1), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl are optionally substituted with 1, 2, or 3 substitutentsindependently selected from Cy², CN, NO₂, OR^(a1), SR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1),NR^(c1)R^(d1), NR^(c1)C(O)R^(b1), NR^(c1)C(O)NR^(c1)R^(d1),NR^(c1)C(O)OR^(a1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1),NR^(c1)S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1);

R^(6a) and R^(6b) are independently selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, Cy², C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), S(O)R^(b1), S(O)NR^(c1)R^(d1),S(O)₂R^(b1), NR^(c1)S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1), wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are optionally substitutedwith 1, 2, or 3 substitutents independently selected from Cy², CN, NO₂,OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)C(O)OR^(a1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), NR^(c1)S(O)₂R^(b1), andS(O)₂NR^(c1)R^(d1);

R^(L1) and R^(L2) are independently selected from halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a2), SR^(a2),C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)C(O)OR^(a2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2), andS(O)₂NR^(c2)R^(d2);

R^(2a) is H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₁₀ alkynyl, C₁₋₆ haloalkyl,C₁₋₆ hydroxyalkyl, C₁₋₆ cyanoalkyl, Cy⁴, CN, NO₂, C(O)R^(bb),C(O)NR^(c6)R^(d6), or C(O)OR^(a6);

Cy is aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, eachoptionally substituted with 1, 2, 3, 4 or 5 substituents selected fromhalo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, CN, NO₂,OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),OC(O)R^(b3), OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3), andS(O)₂NR^(c3)R^(d3);

Cy¹ and Cy² are independently selected from aryl, heteroaryl,cycloalkyl, and heterocycloalkyl, each optionally substituted with 1, 2,3, 4 or 5 substituents selected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, C₁₋₄ haloalkyl, CN, NO₂, OR^(a4), SR^(a4), C(O)R^(b4),C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4),NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4), S(O)R^(b4),S(O)NR^(c4)R^(d4), S(O)₂R^(b4), S(O)₂NR^(c4)R^(d4), and Cy³, whereinsaid C₁₋₄ alkyl, C₂₋₄ alkenyl, or C₂₋₄ alkynyl is optionally substitutedwith 1, 2, or 3 substituents independently selected from CN, NO₂, halo,OR^(a4), SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4),OC(O)R^(b4), OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4),S(O)₂NR^(c4)R^(d4), and Cy³;

Cy³ and Cy⁴ are independently selected from aryl, heteroaryl,cycloalkyl, and heterocycloalkyl, each optionally substituted with 1, 2,3, 4 or 5 substituents selected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, C₁₋₄ haloalkyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, CN, NO₂, OR^(a6), SR^(a6), C(O)R^(b6),C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6), OC(O)NR^(c6)R^(d6),NR^(c6)R^(d6), NR^(c6)C(O)R^(b6), NR^(c6)C(O)OR^(a6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), and S(O)₂NR^(c6)R^(d6);

Z is aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, each optionallysubstituted with 1, 2, 3, 4 or 5 substituents selected from halo, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, CN, NO₂, OR^(a6),SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6),OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)OR^(a6), S(O)R^(b6), S(O)NR^(c6)R^(d6), S(O)₂R^(b6), andS(O)₂NR^(c6)R^(d6);

R^(A) is H or C₁₋₄ alkyl;

Q¹ and Q² are independently selected from O, S, NH, CH₂, CO, CS, SO,SO₂, OCH₂, SCH₂, NHCH₂, CH₂CH₂, COCH₂, CONH, COO, SOCH₂, SONH, SO₂CH₂,and SO₂NH;

R^(a) and R^(a1) are independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and Cy², wherein said C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl, is optionally substitutedwith 1, 2, 3, 4, or 5 substituents selected from halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, C₁₋₆cyanoalkyl, Cy², CN, NO₂, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), NR^(c5)C(O)NR^(c5)R^(d5),NR^(c5)C(O)OR^(a5), S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5),NR^(c5)S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5);

R^(a2), R^(a3), R^(a4), R^(a5), and R^(a6) are independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl or heterocycloalkylalkyl, wherein said C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl orheterocycloalkylalkyl is optionally substituted with OH, cyano, amino,halo, C₁₋₆ alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,cycloalkyl or heterocycloalkyl;

R^(b) and R^(b1) are independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and Cy², wherein said C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl, is optionally substitutedwith 1, 2, 3, 4, or 5 substituents selected from halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, C₁₋₆cyanoalkyl, Cy², CN, NO₂, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), NR^(c5)C(O)NR^(c5)R^(d5),NR^(c5)C(O)OR^(a5), S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5),NR^(c5)S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5);

R^(b2), R^(b3), R^(b4), R^(b5), and R^(b6) are independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl or heterocycloalkylalkyl, wherein said C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl orheterocycloalkylalkyl is optionally substituted with OH, cyano, amino,halo, C₁₋₆ alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,cycloalkyl or heterocycloalkyl;

R^(c) and R^(d) are independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and Cy², wherein said C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl, is optionally substitutedwith 1, 2, 3, 4, or 5 substituents independently selected from halo,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆hydroxyalkyl, C₁₋₆ cyanoalkyl, Cy², CN, NO₂, OR^(a5), SR^(a5),C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5),OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5), S(O)R^(b5),S(O)NR^(c5)R^(d5), S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5), andS(O)₂NR^(c5)R^(d5);

or R^(c) and R^(d) together with the N atom to which they are attachedform a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionallysubstituted with 1, 2, or 3 substituents independently selected fromhalo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆hydroxyalkyl, C₁₋₆ cyanoalkyl, Cy², CN, NO₂, OR^(a5), SR^(a5),C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5),OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(d5), S(O)R^(b5),S(O)NR^(c5)R^(d5), S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5), andS(O)₂NR^(c5)R^(d5);

R^(c1) and R^(d1) are independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and Cy², wherein said C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl, is optionally substitutedwith 1, 2, 3, 4, or 5 substituents independently selected from halo,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆hydroxyalkyl, C₁₋₆ cyanoalkyl, Cy², CN, NO₂, OR^(a5), SR^(a5),C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5),OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(d5), S(O)R^(b5),S(O)NR^(c5)R^(d5), S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5), andS(O)₂NR^(c5)R^(d5);

or R^(c1) and R^(d1) together with the N atom to which they are attachedform a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionallysubstituted with 1, 2, or 3 substituents independently selected fromhalo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆hydroxyalkyl, C₁₋₆ cyanoalkyl, Cy², CN, NO₂, OR^(a5), SR^(a5),C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5),OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(d5), S(O)R^(b5),S(O)NR^(c5)R^(d5), S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5), andS(O)₂NR^(c5)R^(d5);

R^(c2) and R^(d2) are independently selected from H, C₁₋₁₀ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, andheterocycloalkylalkyl, wherein said C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl isoptionally substituted with OH, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl orheterocycloalkyl;

or R^(c2) and R^(d2) together with the N atom to which they are attachedform a 4-, 5-, 6- or 7-membered heterocycloalkyl group;

R^(c3) and R^(d3) are independently selected from H, C₁₋₁₀ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, andheterocycloalkylalkyl, wherein said C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl isoptionally substituted with OH, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl orheterocycloalkyl;

or R^(c3) and R^(d3) together with the N atom to which they are attachedform a 4-, 5-, 6- or 7-membered heterocycloalkyl group;

R^(c4) and R^(d4) are independently selected from H, C₁₋₁₀ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, andheterocycloalkylalkyl, wherein said C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl isoptionally substituted with OH, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl orheterocycloalkyl;

or R^(c4) and R^(d4) together with the N atom to which they are attachedform a 4-, 5-, 6- or 7-membered heterocycloalkyl group;

R^(c5) and R^(d5) are independently selected from H, C₁₋₁₀ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, andheterocycloalkylalkyl, wherein said C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl isoptionally substituted with OH, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl orheterocycloalkyl;

or R^(c5) and R^(d5) together with the N atom to which they are attachedform a 4-, 5-, 6- or 7-membered heterocycloalkyl group; and

R^(c6) and R^(d6) are independently selected from H, C₁₋₁₀ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, andheterocycloalkylalkyl, wherein said C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl isoptionally substituted with OH, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl orheterocycloalkyl;

or R^(c6) and R^(d6) together with the N atom to which they are attachedform a 4-, 5-, 6- or 7-membered heterocycloalkyl group; and

m, p, q, and r are independently selected from 0 and 1.

In some embodiments, when X

Y is CR^(4a)R^(5a)—CR^(4a)R^(5b), then R² is other than halo, C₁₋₃haloalkyl, Z or SR^(A).

In some embodiments, when X

Y is CR^(3a)═N, then R² is other than Z;

In some embodiments, when X

Y is N═CR^(3b) and R^(3b) is H or unsubstituted aryl, then R² is otherthan unsubstituted aryl;

In some embodiments, when X

Y is N═N, then R² is other than aryl; and

In some embodiments, when X

Y is CR^(3a)═CR^(3b), then -L-R1 is other than methyl.

In some embodiments, when X is CR^(4a)R^(5a) and Y is CR^(4b)R^(5b),then R² is other than halo or C₁ trihaloalkyl.

In some embodiments, when X is CR^(4a)R^(5a) and Y is CR^(4b)R^(5b),then R² is other than Br or C₃ trihaloalkyl.

In some embodiments, X

Y is other than CR^(4a)R^(5a)—CR^(4b)R^(5b).

In some embodiments, R^(3a) and R^(3b) are independently selected fromH, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆hydroxyalkyl, C₁₋₆ cyanoalkyl, Cy¹, CN, NO₂, OR^(a), SR^(a), C(O)R^(b),C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl is optionallysubstituted with 1, 2, or 3 substitutents independently selected fromCy¹, CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a),OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a), S(O)R^(b), S(O)NR^(c)R^(d),S(O)₂R^(b), NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments, Cy¹ and Cy² are independently selected from aryl,heteroaryl, cycloalkyl, and heterocycloalkyl, each optionallysubstituted with 1, 2, 3, 4 or 5 substituents selected from halo, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, CN, NO₂, OR^(a4),SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4),OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4),S(O)₂NR^(c4)R^(d4), and Cy³, wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, orC₂₋₄ alkynyl is optionally substituted with 1, 2, or 3 substituentsindependently selected from CN, NO₂, OR^(a4), SR^(a4), C(O)R^(b4),C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4),NR^(c4)R^(d4), NR^(c)C(O)R^(b4), NR^(c4)C(O)OR^(a4), S(O)R^(b4),S(O)NR^(c4)R^(d4), S(O)₂R^(b4), S(O)₂NR^(c4)R^(d4), and Cy³.

In some embodiments, X is N.

In some embodiments, X is CR³a.

In some embodiments, X is CR^(4a)R^(5a).

In some embodiments, X is CH.

In some embodiments, Y is N.

In some embodiments, Y is CR^(3b).

In some embodiments, Y is CH.

In some embodiments, Y is C-Me.

In some embodiments, Y is CR^(4b)R^(5b).

In some embodiments, X is N and Y is CR^(3b).

In some embodiments, X is CR^(3a) and Y is N.

In some embodiments, X is CH and Y is N.

In some embodiments, X and Y are both N.

In some embodiments, at least one of X and Y is N.

In some embodiments, R^(3a) and R^(3b) are independently selected fromH, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆hydroxyalkyl, Cy¹, OR^(a), SR^(a), S(O)R^(b), S(O)₂R^(b), andNR^(c)R^(d), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl areoptionally substituted with 1, 2, or 3 substitutents independentlyselected from Cy¹, CN, NO₂, halo, OR^(a), SR^(a), C(O)R^(b),C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments, R^(3a) and R^(3b) are independently selected fromH, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆hydroxyalkyl, Cy¹, OR^(a), SR^(a), and NR^(c)R^(d), wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are optionally substituted with 1,2, or 3 substitutents independently selected from Cy¹, CN, NO₂, OR^(a),SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d),NR^(c)C(O)OR^(a), S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b),NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments, R^(3a) and R^(3b) are independently selected fromH, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆hydroxyalkyl, Cy¹, OR^(a), SR^(a), and NR^(c)R^(d), wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are optionally substituted with 1,2, or 3 substitutents independently selected from Cy¹, C(O)NR^(c)R^(d),C(O)OR^(a), and NR^(c)C(O)R^(b).

In some embodiments, R^(3a) and R^(3b) are independently selected fromH, C₁₋₆ alkyl, C₁₋₆ haloalkyl, Cy¹, OR^(a), SR^(a), S(O)R^(b),S(O)₂R^(b), and NR^(c)R^(d), wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, or 3 substitutents independently selected fromCy¹, C(O)NR^(c)R^(d), C(O)OR^(a), halo, OR^(a), NR^(c)R^(d),NR^(c)C(O)NR^(c)R^(d), and NR^(c)C(O)R^(b).

In some embodiments:

at least one of R^(3a) and R^(3b) is selected from Cy¹;

Cy¹ is selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl,each optionally substituted with 1, 2, 3, 4 or 5 substituents selectedfrom halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,OR^(a4), SR^(a4), SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4),and Cy³, wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl areoptionally substituted with 1, 2, or 3 substituents independentlyselected from halo, OR^(a4) and Cy³; and

Cy³ is selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl,each optionally substituted with 1, 2, 3, 4 or 5 substituents selectedfrom halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, aryl,heteroaryl, CN, NO₂, NR^(c6)R^(d6), OR^(a6), and SR^(a6).

In some embodiments, at least one of R^(3a) and R^(3b) is selected fromC₁₋₆ alkyl and C₁₋₆ haloalkyl, wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, or 3 substitutents independently selected fromC(O)NR^(c)R^(d), C(O)OR^(a), NR^(c)R^(d), NR^(c)C(O)NR^(c)R^(d), andNR^(c)C(O)R^(b).

In some embodiments:

at least one of R^(3a) and R^(3b) is selected from C₁₋₃ alkyl, whereinsaid C₁₋₃ alkyl is substituted with Cy¹ and optionally substituted with1 or 2 substitutents independently selected from halo, OR^(a), andSR^(a);

Cy¹ is selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl,each optionally substituted with 1, 2, 3, 4 or 5 substituents selectedfrom halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, CN,NO₂, OR^(a4), SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4),OC(O)R^(b4), OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4),S(O)₂NR^(c4)R^(d4), and Cy³, wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, andC₂₋₄ alkynyl are optionally substituted with 1, 2, or 3 substituentsindependently selected from halo, OR^(a4) and Cy³; and

Cy³ is selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl,each optionally substituted with 1, 2, 3, 4 or 5 substituents selectedfrom halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, aryl,heteroaryl, cycloalkyl, heterocycloalkyl, CN, NO₂, OR^(a6), SR^(a6),C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6),OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)OR^(a6), S(O)R^(b6), S(O)NR^(c6)R^(d6), S(O)₂R^(b6), andS(O)₂NR^(c6)R^(d6).

In some embodiments:

at least one of R^(3a) and R^(3b) is selected from C₁₋₃ alkyl, whereinsaid C₁₋₃ alkyl is substituted with Cy¹ and optionally substituted with1 or 2 substitutents independently selected from halo, OR^(a), andSR^(a);

Cy¹ is selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl,each optionally substituted with 1, 2, 3, 4 or 5 substituents selectedfrom halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, CN,NO₂, OR^(a4), SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), andCy³, wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl areoptionally substituted with 1, 2, or 3 substituents independentlyselected from halo, OR^(a4) and Cy³; and

Cy³ is selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl,each optionally substituted with 1, 2, 3, 4 or 5 substituents selectedfrom halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, aryl,heteroaryl, CN, NO₂, NR^(c6)R^(d6), OR^(a6), and SR^(a6).

In some embodiments:

at least one of R^(3a) and R^(3b) is selected from C₁₋₃ alkyl, whereinsaid C₁₋₃ alkyl is substituted with Cy¹ and optionally substituted with1 or 2 substitutents independently selected from halo, OR^(a), andSR^(a);

Cy¹ is selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl,each substituted with 1 or 2 R⁷ and optionally substituted by 1, 2, or 3R⁸;

R⁷ is, at each occurrence, independently selected from Cy³ and C₁₋₄alkyl, wherein said C₁₋₄ alkyl is substituted with 1 or 2 Cy³ andoptionally substituted with 1 or 2 substituents independently selectedfrom halo and OR^(a4);

R⁸ is, at each occurrence, independently selected from halo, C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, CN, NO₂, OR^(a4), SR^(a4),C(O)R^(b4), C(O)NR^(c4)R^(d4), and C(O)OR^(a4); and

Cy³ is selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl,each optionally substituted with 1, 2, 3, 4 or 5 substituents selectedfrom halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, aryl,heteroaryl, CN, NO₂, NR^(c6)R^(d6), OR^(a6), and SR^(a6).

In some embodiments, at least one of R^(3a) and R^(3b) is -L^(A)-Cy¹,wherein L^(A) is C₁₋₃ alkylene optionally substituted with 1 or 2substitutents independently selected from halo, OR^(a), and SR^(a). Insome further embodiments, Cy¹ is aryl or heteroaryl, each optionallysubstituted by 1, 2, or 3 substituents independently selected from Cy³,halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, CN, NO₂,OR^(a4), SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), and C(O)OR^(a4). In yetfurther embodiments, Cy¹ is 1,2,4-oxadiazolyl optionally substituted by1, 2, or 3 substituents independently selected from Cy³, halo, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, CN, NO₂, OR^(a4),SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), and C(O)OR^(a4).

In some embodiments, one of R^(3a) and R^(3b) is L^(A)Cy¹, and the otheris selected from H, C₁₋₄ alkyl, and C₁₋₄ haloalkyl.

In some embodiments, at least one of R^(3a) and R^(3b) is-L^(A)-Cy¹-(L^(B))_(t1)-Cy³, wherein L^(A) is C₁₋₃ alkylene optionallysubstituted with 1 or 2 substitutents independently selected from halo,OR^(a), and SR^(a); L^(B) is C₁₋₄ alkylene optionally substituted with 1or 2 substitutents independently selected from halo and OR^(a4); and t1is 0 or 1. In some further embodiments, L^(A) is C₁₋₃ alkyleneoptionally substituted with OH. In yet embodiments, L^(A) is C₂₋₃alkylene optionally substituted with OH. In further embodiments, L^(A)is C₂₋₃ alkylene. In some embodiments, t1 is 0. In some embodiments, t1is 1. In some embodiments, L^(B) is C₁₋₄ alkylene optionally substitutedwith OH. In some further embodiments, L^(B) is C₁₋₃ alkylene optionallysubstituted with OH.

In some embodiments, at least one of R^(3a) and R^(3b) is-L^(A)-Cy¹-(L^(B))_(t1)-Cy³, wherein L^(A) is C₁₋₃ alkylene optionallysubstituted with 1 or 2 substitutents independently selected from haloand OR^(a). In some further embodiments, L^(A) is C₁₋₃ alkyleneoptionally substituted with halo or OH.

In some embodiments, at least one of R^(3a) and R^(3b) is-L^(A)-Cy¹-(L^(B))_(t1)-Cy³, wherein L^(B) is C₁₋₄ alkylene optionallysubstituted with 1 or 2 substitutents independently selected from haloand OR^(a4). In some further embodiments, L^(B) is C₁₋₄ alkyleneoptionally substituted with halo or OH.

In some embodiments, at least one of R^(3a) and R^(3b) is-L^(A)-Cy¹-(L^(B))_(t1)-Cy³; and Cy¹ is aryl or heteroaryl, eachoptionally substituted by 1, 2, or 3 substituents independently selectedfrom Cy³, halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,CN, NO₂, OR^(a4), SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), andC(O)OR^(a4). In some further embodiments, Cy¹ is 1,2,4-oxadiazolyl. Insome embodiments, Cy³ is selected from aryl and heteroaryl, eachoptionally substituted with 1, 2, 3, 4 or 5 substituents selected fromhalo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, aryl,heteroaryl, NR^(c6)R^(d6), and OR^(a4). In some further embodiments, Cy³is selected from aryl and heteroaryl, each substituted by OH andoptionally substituted with 1, 2, or 3 substituents selected from halo,C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, aryl,heteroaryl, NR^(c6)R^(d6) and OR^(a6).

In some embodiments, one of R^(3a) and R^(3b) is-L^(A)-Cy¹-(L^(B))_(t1)-Cy³, and the other is selected from H, C₁₋₄alkyl, and C₁₋₄ haloalkyl.

In some embodiments, R^(3a) and R^(3b) are independently selected fromH, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl.

In some embodiments, R^(3a) and R^(3b) are independently selected fromH, halo, and C₁₋₆ alkyl.

In some embodiments, R^(3a) and R^(3b) are independently selected from Hand C₁₋₄ alkyl. In some further embodiments, R^(3a) and R^(3b) areindependently selected from H and methyl. In yet further embodiments,R^(3a) or R^(3b) is methyl.

In some embodiments, one of R^(3a) and R^(3b) is selected from aryl,heteroaryl, cycloalkyl, and heterocycloalkyl.

In some embodiments, R^(3a) and R^(3b) are independently selected fromaryl, heteroaryl, cycloalkyl, and heterocycloalkyl.

In some embodiments, R^(3b) is selected from aryl, heteroaryl,cycloalkyl, and heterocycloalkyl, each optionally substituted with 1, 2,3, 4 or 5 substituents selected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, C₁₋₄ haloalkyl, OR^(a4), SR^(a4), C(O)R^(b4),C(O)NR^(c4)R^(d4), C(O)OR^(a4), and Cy³, wherein said C₁₋₄ alkyl, C₂₋₄alkenyl, and C₂₋₄ alkynyl are optionally substituted with 1, 2, or 3substituents independently selected from halo, OR^(a4) and Cy³; and Cy³is selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl,each optionally substituted with 1, 2, 3, 4 or 5 substituents selectedfrom halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, aryl,heteroaryl, CN, NO₂, NR^(c6)R^(d6), OR^(a6), and SR^(a6).

In some embodiments, R^(3b) is heteroaryl that is optionally substitutedwith 1, 2, 3, 4, or 5 substituents independently selected from aryl,cycloalkyl, and heterocycloalkyl, each optionally substituted by 1, 2,3, 4 or 5 substituents selected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, C₁₋₄ haloalkyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, CN, NO₂, OR^(a6), and SR^(a6).

In some embodiments, R^(3b) is thiazolyl that is optionally substitutedwith phenyl, wherein said phenyl is optionally substituted with 1, 2, 3,4, or 5 substituents independently selected from OH and halo.

In some embodiments, m and q are both 0.

In some embodiments, m is 0.

In some embodiments, q is 0.

In some embodiments, m is 1.

In some embodiments, q is 1.

In some embodiments, p is 1.

In some embodiments, r is 1.

In some embodiments, p is 0.

In some embodiments, r is 0.

In some embodiments, L is —(C₁₋₁₈ alkylene)- optionally substituted by1, 2, 3, 4, or 5 R^(L1). In some further embodiments, each R^(L1) isindependent selected from halo, OH, and CN. In yet further embodiments,each R^(L1) is independent halo.

In some embodiments, L is C₁₋₆ alkylene optionally substituted by 1, 2,3, 4, or 5 R^(L1). In some further embodiments, each R^(L1) isindependent selected from halo, OH, and CN. In yet further embodiments,each R^(L1) is independent halo.

In some embodiments, L is —(C₁₋₁₈ alkylene)-. In some furtherembodiments, L is C₁₋₆ alkylene.

In some embodiments, R¹ is H, C₁₋₁₀ alkyl, or Cy, wherein said C₁₋₁₀alkyl is optionally substituted with 1, 2, 3, 4, or 5 R^(L2).

In some embodiments, R¹ is H, C₁₋₁₀ alkyl optionally substituted with 1,2, 3, 4, or 5 R^(L2).

In some embodiments, R¹ is H or C₁₋₃ alkyl, wherein said C₁₋₃ alkyl isoptionally substituted with 1, 2, 3, 4, or 5 R^(L2). In some furtherembodiments, R^(L2) is, at each occurrence, independently selected fromhalo, CN, NO₂, and OR^(a2). In yet further embodiments, each R^(L2) isindependent halo.

In some embodiments, R¹ is H or C₁₋₁₀ alkyl.

In some embodiments, R¹ is Cy.

In some embodiments, -L-R¹ is C₁₋₁₀ alkyl.

In some embodiments, -L-R¹ is C₁₋₇ alkyl optionally substituted with 1,2, 3, 4 or 5 halo. In some embodiments, -L-R¹ is C₃₋₇ alkyl optionallysubstituted with 1, 2, 3, 4 or 5 halo. In some embodiments, -L-R¹ isC₂₋₆ alkyl optionally substituted with 1, 2, 3, 4 or 5 halo. In someembodiments, -L-R¹ is C₂₋₆ alkyl. In some embodiments, -L-R¹ is C₃₋₇alkyl.

In some embodiments, -L-R¹ is C₄₋₇ alkyl optionally substituted with 1,2, 3, 4 or 5 halo.

In some embodiments, -L-R¹ is butyl or pentyl.

In some embodiments, R² is halo, cyano, C₁ haloalkyl, Z, SR^(A), or amoiety having the formula:

In some embodiments, R² is halo, cyano, C₁ haloalkyl, Z, or, SR^(A).

In some embodiments, R² is halo, cyano, C₁ haloalkyl, or a moiety havingthe formula:

In some embodiments, R² is halo, cyano, or C₁₋₃ haloalkyl.

In some embodiments, R² is halo or C₁₋₃ haloalkyl.

In some embodiments, R² is Cl, Br, or CF₃.

In some embodiments, R² is C₁₋₃ haloalkyl. In some further embodiments,R² is CF₃ or CF₂CF₃. In yet further embodiments, R² is CF₃. In someother embodiments, R² is CF₂CF₃.

In some embodiments, R² is C₁ haloalkyl.

In some embodiments, R² is halo. In some further embodiments, R² is Clor Br.

In some embodiments, R² is Br.

In some embodiments, R² is Cl.

In some embodiments, R² is CF₃.

In some embodiments, R² is a moiety having the formula:

In some embodiments, R² is S-Me.

In some embodiments, R² is selected from aryl, heteroaryl, cycloalkyl,and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5substituents selected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₁₋₄ haloalkyl, and OR^(a4).

In some embodiments, R^(2a) is H (i.e., R² is acetylenyl).

-   -   In some embodiments, R^(4a), R^(4b), R^(5a), and R^(5b) are        independently selected from H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,        C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, and C₁₋₆ cyano        alkyl.

In some embodiments, R^(L1) and R^(L2) are independently selected fromhalo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂,and OR^(a2).

In some embodiments, Cy is aryl optionally substituted by 1, 2, 3, 4 or5 substituents selected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ haloalkyl, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3),C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3).

In some embodiments, Cy is aryl.

In some embodiments, Cy is heteroaryl optionally substituted by 1, 2, 3,4 or 5 substituents selected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ haloalkyl, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3),C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR⁶C(O)OR^(a3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3).

In some embodiments, Cy is heteroaryl.

In some embodiments, Cy is cycloalkyl optionally substituted by 1, 2, 3,4 or 5 substituents selected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ haloalkyl, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3),C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3).

In some embodiments, Cy is cycloalkyl.

In some embodiments, Cy is heterocycloalkyl optionally substituted by 1,2, 3, 4 or 5 substituents selected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, C₁₋₄ haloalkyl, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3),C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR⁶C(O)OR^(a3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3).

In some embodiments, Cy is heterocycloalkyl.

In some embodiments, Cy¹ and Cy² are independently selected from aryl,heteroaryl, cycloalkyl, and heterocycloalkyl, each optionallysubstituted by 1, 2, 3, 4 or 5 substituents selected from halo, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, CN, NO₂, OR^(a4),SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4),OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4), andS(O)₂NR^(c4)R^(d4).

In some embodiments, Cy¹ is selected from aryl, heteroaryl, cycloalkyl,and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5substituents selected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₁₋₄ haloalkyl, CN, NO₂, OR^(a4), SR^(a4), C(O)R^(b4),C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4),NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4), S(O)R^(b4),S(O)NR^(c4)R^(d4), S(O)₂R^(b4), S(O)₂NR^(c4)R^(d4), and Cy³, whereinsaid C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl are optionallysubstituted by 1, 2, or 3 substituents independently selected from halo,OR^(a4) and Cy³.

In some embodiments, Cy¹ is selected from aryl, heteroaryl, cycloalkyl,and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5substituents selected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₁₋₄ haloalkyl, CN, NO₂, OR^(a4), SR^(a4), C(O)R^(b4),C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4),NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4), S(O)R^(b4),S(O)NR^(c4)R^(d4), S(O)₂R^(b4), S(O)₂NR^(c4)R^(d4), and Cy³, whereinsaid C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl are optionallysubstituted by 1, 2, or 3 substituents independently selected fromOR^(a4) and Cy³.

In some embodiments, Cy¹ is selected from aryl, heteroaryl, cycloalkyl,and heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5substituents selected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₁₋₄ haloalkyl, CN, NO₂, OR^(a4), SR^(a4), C(O)R^(b4),C(O)NR^(c4)R^(d4), C(O)OR^(a4), and Cy³, wherein said C₁₋₄ alkyl, C₂₋₄alkenyl, and C₂₋₄ alkynyl are optionally substituted with 1, 2, or 3substituents independently selected from halo, OR^(a4) and Cy³.

In some embodiments, Cy¹ is selected from aryl, heteroaryl, cycloalkyl,and heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5substituents selected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₁₋₄ haloalkyl, CN, NO₂, OR^(a4), SR^(a4), C(O)R^(b4),C(O)NR^(c4)R^(d4), C(O)OR^(a4), and Cy³, wherein said C₁₋₄ alkyl, C₂₋₄alkenyl, and C₂₋₄ alkynyl are optionally substituted with 1, 2, or 3substituents independently selected from OR^(a4) and Cy³.

In some embodiments, Cy³ is selected from aryl, heteroaryl, cycloalkyl,and heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5substituents selected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₁₋₄ haloalkyl, aryl, heteroaryl, CN, NO₂, NR^(c6)R^(d6), OR^(a6), andSR^(a6).

In some embodiments, Cy³ is selected from aryl or heteroaryl, eachoptionally substituted with 1, 2, 3, 4 or 5 substituents selected fromhalo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, aryl,heteroaryl, CN, NO₂, NR^(c6)R^(d6), OH, —O—(C₁₋₄ alkyl) and —O—(C₁₋₄haloalkyl).

In some embodiments, Cy³ is selected from aryl or heteroaryl, eachoptionally substituted with 1, 2, 3, 4 or 5 substituents selected fromhalo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, CN, NO₂,NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, OH, —O—(C₁₋₄ alkyl) and —O—(C₁₋₄haloalkyl).

In some embodiments, the compounds of the invention have Formula II:

wherein constituent members are provided herein.

In some embodiments, the compounds of the invention have Formula II,wherein -L-R¹ is C₁₋₇ alkyl optionally substituted with 1, 2, 3, 4 or 5halo. In some further embodiments, -L-R¹ is C₂₋₇ alkyl optionallysubstituted with 1, 2, 3, 4 or 5 halo. In some further embodiments,-L-R¹ is C₃₋₆ alkyl optionally substituted with 1, 2, 3, 4 or 5 halo. Insome further embodiments, -L-R¹ is C₃₋₆ alkyl. In some furtherembodiments, -L-R¹ is butyl or pentyl.

In some embodiments, the compounds of the invention have Formula II,wherein R² is halo. In some further embodiments, R² is Cl or Br. In yetfurther embodiments, R² is Br. In other further embodiments, R² is Cl.

In some embodiments, the compounds of the invention have Formula II,wherein R^(3b) is selected from H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, Cy¹, OR^(a), SR^(a),S(O)R^(b), S(O)₂R^(b), and NR^(c)R^(d), wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl are optionally substituted with 1, 2, or 3substitutents independently selected from Cy¹, CN, NO₂, halo, OR^(a),SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d),NR^(c)C(O)OR^(a), S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b),NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments, the compounds of the invention have Formula II,wherein R^(3b) is selected from H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, Cy¹, OR^(a), SR^(a),S(O)R^(b), S(O)₂R^(b), and NR^(c)R^(d), wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl are optionally substituted with 1, 2, or 3substitutents independently selected from Cy¹, CN, NO₂, OR^(a), SR^(a),C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d),NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a),S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b), NR^(c)S(O)₂R^(b), andS(O)₂NR^(c)R^(d).

In some embodiments, the compounds of the invention have Formula II,wherein R^(3b) is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, Cy¹,OR^(a), SR^(a), S(O)R^(b), S(O)₂R^(b), and NR^(c)R^(d), wherein saidC₁₋₆ alkyl is optionally substituted with 1, 2, or 3 substitutentsindependently selected from Cy¹, C(O)NR^(c)R^(d), C(O)OR^(a), halo,OR^(a), NR^(c)R^(d), NR^(c)C(O)NR^(c)R^(d), and NR^(c)C(O)R^(b). In somefurther embodiments, R^(3b) is C₁₋₃ alkyl. In yet further embodiments,R^(3b) is methyl.

In some embodiments, the compounds of the invention have Formula II,wherein:

R^(3b) is Cy¹;

Cy¹ is selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl,each optionally substituted with 1, 2, 3, 4 or 5 substituents selectedfrom halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,OR^(a4), SR^(a4), C(O)R^(b4), C(O)NR^(c)R^(d4), C(O)OR^(a4), and Cy³,wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl are optionallysubstituted with 1, 2, or 3 substituents independently selected fromhalo, OR^(a4) and Cy³; and

Cy³ is selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl,each optionally substituted with 1, 2, 3, 4 or 5 substituents selectedfrom halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, aryl,heteroaryl, CN, NO₂, NR^(c6)R^(d6), OR^(a6), and SR^(a6).

In some embodiments, the compounds of the invention have Formula II,wherein R^(3b) is C₁₋₆ alkyl or C₁₋₆ haloalkyl, wherein said C₁₋₆ alkylis optionally substituted with 1, 2, or 3 substitutents independentlyselected from C(O)NR^(c)R^(d), C(O)OR^(a), NR^(c)R^(d),NR^(c)C(O)NR^(c)R^(d), and NR^(c)C(O)R^(b).

In some embodiments, the compounds of the invention have Formula II,wherein:

R^(3b) is selected from C₁₋₃ alkyl, wherein said C₁₋₃ alkyl issubstituted with Cy¹ and optionally substituted with 1 or 2substitutents independently selected from halo, OR^(a), and SR^(a);

Cy¹ is selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl,each substituted with 1 or 2 R⁷ and optionally substituted by 1, 2, or 3R⁸;

R⁷ is, at each occurrence, independently selected from Cy³ and C₁₋₄alkyl, wherein said C₁₋₄ alkyl is substituted with 1 or 2 Cy³ andoptionally substituted with 1 or 2 substituents independently selectedfrom halo and OR^(a4);

R⁸ is, at each occurrence, independently selected from halo, C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, CN, NO₂, OR^(a4), SR^(a4),C(O)R^(b4), C(O)NR^(c4)R^(d4), and C(O)OR^(a4); and

Cy³ is selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl,each optionally substituted with 1, 2, 3, 4 or 5 substituents selectedfrom halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, aryl,heteroaryl, CN, NO₂, NR^(c6)R^(d6), OR^(a6), and SR^(a6).

In some embodiments, the compounds of the invention have Formula II,wherein:

L is C₁₋₆ alkylene;

R¹ is H or C₁₋₃ alkyl, wherein said C₁₋₃ alkyl is optionally substitutedwith 1, 2, 3, 4, or 5 R^(L2); and

R^(L2) is, at each occurrence, independently selected from halo, CN,NO₂, and OR^(a2).

In some embodiments, the compounds of the invention have Formula II,wherein R² is halo or C₁₋₃ haloalkyl.

In some embodiments, the compounds of the invention have Formula II,wherein R² is Br.

In some embodiments, the compounds of the invention have Formula II,wherein: L is C₁₋₁₈ alkylene;

R^(3b) is H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₁₋₆ hydroxyalkyl, Cy¹, OR^(a), SR^(a), or NR^(c)R^(d),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are optionallysubstituted with 1, 2, or 3 substitutents independently selected fromCy¹, CN, NO₂, halo, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d),C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a), S(O)R^(b), S(O)NR^(c)R^(d),S(O)₂R^(b), NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d); and

R² is halo, cyano, C₁ haloalkyl, Z, SR^(A), or a moiety having theformula:

In some embodiments, the compounds of the invention have Formula II,wherein:

L is C₁₋₁₈ alkylene;

R^(3b) is H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₁₋₆ hydroxyalkyl, Cy¹, OR^(a), SR^(a), or NR^(c)R^(d),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are optionallysubstituted with 1, 2, or 3 substitutents independently selected fromCy¹, CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a),OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a), S(O)R^(b), S(O)NR^(c)R^(d),S(O)₂R^(b), NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d); and

R² is halo, cyano, C₁ haloalkyl, Z, SR^(A), or a moiety having theformula:

In some embodiments, the compounds of the invention have Formula II,wherein:

L is C₁₋₁₈ alkylene;

R^(3b) is H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₁₋₆ hydroxyalkyl, Cy¹, OR^(a), SR^(a), or NR^(c)R^(d),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are optionallysubstituted with 1, 2, or 3 substitutents independently selected fromCy¹, halo, OR^(a), C(O)NR^(c)R^(d), C(O)OR^(a), and NR^(c)C(O)R^(b); and

R² is halo, cyano, C₁ haloalkyl, Z, SR^(A), or a moiety having theformula:

In some embodiments, the compounds of the invention have Formula II,wherein:

L is C₁₋₁₈ alkylene;

R^(3b) is heteroaryl that is optionally substituted with 1, 2, 3, 4, or5 substituents independently selected from aryl, cycloalkyl, andheterocycloalkyl, wherein said aryl, cycloalkyl, or heterocycloalkyl isoptionally substituted by 1, 2, 3, 4 or 5 substituents selected fromhalo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, aryl,heteroaryl, cycloalkyl, heterocycloalkyl, CN, NO₂, OR^(a4), SR^(a6), and

R² is halo, cyano, C₁ haloalkyl, Z, SR^(A), or a moiety having theformula:

In some embodiments, the compounds of the invention have Formula II,wherein:

L is C₁₋₁₈ alkylene;

R^(3b) is thiazolyl that is optionally substituted with phenyl, whereinsaid phenyl is optionally substituted with 1, 2, 3, 4, or 5 substituentsindependently selected from OH and halo and

R² is halo, cyano, C₁ haloalkyl, Z, SR^(A), or a moiety having theformula:

In some embodiments, the compounds of the invention have Formula II,wherein:

L is C₁₋₁₈ alkylene;

R^(3b) is H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, or C₁₋₆haloalkyl; and

R² is halo, cyano, or C₁ haloalkyl.

In some embodiments, the compounds of the invention have Formula II,wherein:

R^(3b) is C₁₋₆ alkyl, C₁₋₆ haloalkyl, or Cy¹, wherein said C₁₋₆ alkyl isoptionally substituted with 1, 2, or 3 substitutents independentlyselected from Cy¹, C(O)NR^(c)R^(d), C(O)OR^(a4), halo, OR^(a), SR^(a),NR^(c)R^(d), NR^(c)C(O)NR^(c)R^(d), and NR^(c)C(O)R^(b);

L is C₁₋₆ alkylene optionally substituted with 1, 2, 3, 4, or 5 R^(L1);

R¹ is H or C₁₋₃ alkyl, wherein said C₁₋₃ alkyl is optionally substitutedwith 1, 2, 3, 4, or 5 R^(L2);

R^(L1) and R^(L2) are, at each occurrence, independently selected fromhalo, CN, NO₂, and OR^(a2); and

R² is halo or C₁₋₃ haloalkyl.

In some embodiments, the compounds of the invention have Formula II,wherein -L-R¹ is C₁₋₇ alkyl optionally substituted with 1, 2, 3, 4 or 5halo; and R² is halo. In some further embodiments, -L-R¹ is C₂₋₇ alkyloptionally substituted with 1, 2, 3, 4 or 5 halo. In some furtherembodiments, R² is Br or Cl. In further embodiments, R² is Br.

In some embodiments, the compounds of the invention have Formula II,wherein -L-R¹ is C₃₋₇ alkyl optionally substituted with 1, 2, 3, 4 or 5halo; and R² is halo. In some further embodiments, -L-R¹ is C₄₋₇ alkyloptionally substituted with 1, 2, 3, 4 or 5 halo. In yet furtherembodiments, -L-R¹ is butyl or pentyl.

In some embodiments, the novel compounds of Formula II have Formula IIa:

wherein L^(A) is C₁₋₃ alkylene optionally substituted with 1 or 2substitutents independently selected from halo, OR^(a), and SR^(a); andwherein Cy¹, L, R¹, and R² are defined as the same as hereinabove.

In some embodiments, the compounds of the invention have Formula IIa,wherein -L-R¹ is C₁₋₇ alkyl optionally substituted with 1, 2, 3, 4 or 5halo. In some further embodiments, -L-R¹ is C₂₋₇ alkyl optionallysubstituted with 1, 2, 3, 4 or 5 halo. In some further embodiments,-L-R¹ is C₃₋₆ alkyl optionally substituted with 1, 2, 3, 4 or 5 halo. Insome further embodiments, -L-R¹ is C₃₋₆ alkyl.

In some embodiments, the compounds of the invention have Formula IIa,wherein -L-R¹ is C₃₋₇ alkyl optionally substituted with 1, 2, 3, 4 or 5halo. In some further embodiments, -L-R¹ is C₄₋₇ alkyl optionallysubstituted with 1, 2, 3, 4 or 5 halo. In yet embodiments, -L-R¹ isbutyl or pentyl.

In some embodiments, the compounds of the invention have Formula IIa,wherein R² is halo or C₁₋₃ haloalkyl. In some further embodiments, R² ishalo. In yet further embodiments, R² is Br.

In some embodiments, the compounds of the invention have Formula IIa,wherein Cy¹ is optionally substituted 1,2,4-oxadiazolyl. In someembodiments, the 1,2,4-oxadiazolyl of Cy¹ is optionally substituted by1, 2, or 3 substituents independently selected from Cy³, halo, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, CN, NO₂, OR^(a4),SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), and C(O)OR^(a4).

In some embodiments, the novel compounds of Formula II have Formula IIb:

wherein:

L^(A) is C₁₋₃ alkylene optionally substituted with 1 or 2 substitutentsindependently selected from halo, OR^(a), and SR^(a);

L^(B) is C₁₋₄ alkylene optionally substituted with 1 or 2 substitutentsindependently selected from halo and OR^(a4);

t1 is 0 or 1; and

Cy¹, Cy³, L, R¹, and R² are defined as the same as hereinabove.

In some embodiments, the compounds of the invention have Formula IIb,wherein -L-R¹ is C₁₋₇ alkyl optionally substituted with 1, 2, 3, 4 or 5halo. In some further embodiments, -L-R¹ is C₂₋₇ alkyl optionallysubstituted with 1, 2, 3, 4 or 5 halo. In some further embodiments,-L-R¹ is C₃₋₆ alkyl optionally substituted with 1, 2, 3, 4 or 5 halo. Insome further embodiments, -L-R¹ is C₃₋₆ alkyl.

In some embodiments, the compounds of the invention have Formula IIb,wherein -L-R¹ is C₃₋₇ alkyl optionally substituted with 1, 2, 3, 4 or 5halo. In some further embodiments, -L-R¹ is C₄₋₇ alkyl optionallysubstituted with 1, 2, 3, 4 or 5 halo. In yet embodiments, -L-R¹ isbutyl or pentyl.

In some embodiments, the compounds of the invention have Formula IIb,wherein R² is halo or C₁₋₃ haloalkyl. In some further embodiments, R² ishalo. In some further embodiments, R² is Cl or Br. In yet furtherembodiments, R² is Br.

In some embodiments, the compounds of the invention have Formula IIb,wherein Cy¹ is 1,2,4-oxadiazolyl.

In some embodiments, the compounds of the invention have Formula IIb,wherein L^(A) is C₁₋₃ alkylene optionally substituted with 1 or 2substitutents independently selected from halo and OH. In some furtherembodiments, L^(A) is C₂₋₃ alkylene optionally substituted with OH. Inyet further embodiments, L^(A) is C₂₋₃ alkylene.

In some embodiments, the compounds of the invention have Formula IIb,wherein L^(A) is C₁₋₃ alkylene optionally substituted with 1 or 2substitutents independently selected from halo and OH. In some furtherembodiments, L^(A) is C₂₋₃ alkylene optionally substituted with 1 or 2halo. In yet further embodiments, L^(A) is C₂₋₃ alkylene optionallysubstituted with halo.

In some embodiments, the compounds of the invention have Formula IIb,wherein t1 is 0. In some embodiments, the compounds of the inventionhave Formula IIb, wherein t1 is 1.

In some embodiments, the compounds of the invention have Formula IIb,wherein t1 is 0.

In some embodiments, the compounds of the invention have Formula IIb,wherein L^(B) is C₁₋₄ alkylene optionally substituted with 1 or 2substitutents independently selected from halo and OH. In some furtherembodiments, L^(B) is C₁₋₃ alkylene optionally substituted with OH.

In some embodiments, the compounds of the invention have Formula IIb,wherein L^(B) is C₁₋₄ alkylene optionally substituted with 1 or 2 halo.In some further embodiments, L^(B) is C₁₋₃ alkylene optionallysubstituted with halo. In some further embodiments, L^(B) is C₁₋₃alkylene.

In some embodiments, the compounds of the invention have Formula IIb,wherein Cy³ is selected from aryl, heteroaryl, cycloalkyl, andheterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5substituents selected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₁₋₄ haloalkyl, aryl, heteroaryl, NR^(c6)R^(d6), and OR^(a6).

In some embodiments, the compounds of the invention have Formula IIb,wherein Cy³ is selected from aryl and heteroaryl, each optionallysubstituted with 1, 2, 3, 4 or 5 substituents selected from halo, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, aryl, heteroaryl,NR^(c6)R^(d6), and OR^(a6). In some further embodiments, Cy³ is selectedfrom aryl and heteroaryl, each substituted by OH and optionallysubstituted with 1, 2, or 3 substituents selected from halo, C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, aryl, heteroaryl,NR^(c6)R^(d6), and OR^(a6).

In some embodiments, the compounds of the invention have Formula III:

wherein constituent members are provided herein. In some furtherembodiments, R² is halo or C₁₋₃ haloalkyl. In yet further embodiments,R² is halo. In still further embodiments, R² is Br. In some embodiments,the compounds of the invention have Formula III, wherein R² is halo.

In some further embodiments, R² is Cl or Br. In yet further embodiments,R² is Br. In other further embodiments, R² is Cl.

In some embodiments, the compounds of the invention have Formula III,wherein -L-R¹ is C₁₋₇ alkyl optionally substituted with 1, 2, 3, 4 or 5halo. In some further embodiments, -L-R¹ is C₂₋₇ alkyl optionallysubstituted with 1, 2, 3, 4 or 5 halo. In some further embodiments,-L-R¹ is C₃₋₆ alkyl optionally substituted with 1, 2, 3, 4 or 5 halo. Insome further embodiments, -L-R¹ is C₃₋₆ alkyl.

In some embodiments, the compounds of the invention have Formula III,wherein -L-R¹ is C₃₋₇ alkyl optionally substituted with 1, 2, 3, 4 or 5halo. In some further embodiments, -L-R¹ is C₄₋₇ alkyl optionallysubstituted with 1, 2, 3, 4 or 5 halo. In yet embodiments, -L-R¹ isbutyl or pentyl.

In some embodiments, the compounds of the invention have Formula IV:

wherein constituent members are provided herein. In some furtherembodiments, R² is halo or C₁₋₃ haloalkyl. In yet further embodiments,R² is halo. In still further embodiments, R² is Br or Cl. In furtherembodiments, R² is Br. In other further embodiments, R² is Cl.

In some embodiments, the compounds of the invention have Formula IV,wherein -L-R¹ is C₁₋₇ alkyl optionally substituted with 1, 2, 3, 4 or 5halo. In some further embodiments, -L-R¹ is C₂₋₇ alkyl optionallysubstituted with 1, 2, 3, 4 or 5 halo. In some further embodiments,-L-R¹ is C₃₋₆ alkyl optionally substituted with 1, 2, 3, 4 or 5 halo. Insome further embodiments, -L-R¹ is C₃₋₆ alkyl.

In some embodiments, the compounds of the invention have Formula IV,wherein -L-R¹ is C₃₋₇ alkyl optionally substituted with 1, 2, 3, 4 or 5halo. In some further embodiments, -L-R¹ is C₄₋₇ alkyl optionallysubstituted with 1, 2, 3, 4 or 5 halo. In yet embodiments, -L-R¹ isbutyl or pentyl. In some embodiments, the compounds of the inventionhave Formula IV, wherein R^(3a) is selected from H, halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, Cy¹,OR^(a), SR^(E), S(O)R^(b), S(O)₂R^(b), and NR^(c)R^(d), wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are optionally substitutedwith 1, 2, or 3 substitutents independently selected from Cy¹, CN, NO₂,halo, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a),OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a), S(O)R^(b), S(O)NR^(c)R^(d),S(O)₂R^(b), NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments, the compounds of the invention have Formula IV,wherein R^(3a) is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, Cy¹,OR^(a), SR^(a), S(O)R^(b), S(O)₂R^(b), and NR^(c)R^(d), wherein saidC₁₋₆ alkyl is optionally substituted with 1, 2, or 3 substitutentsindependently selected from Cy¹, C(O)NR^(c)R^(d), C(O)OR^(a), halo,OR^(a), NR^(c)R^(d), NR^(c)C(O)NR^(c)R^(d), and NR^(c)C(O)R^(b). In somefurther embodiments, R^(3a) is selected from H and C₁₋₆ alkyl. In yetfurther embodiments, R^(3a) is selected from H and methyl.

In some embodiments, the compounds of the invention have Formula IV,wherein:

R^(3a) is Cy¹;

Cy¹ is selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl,each optionally substituted with 1, 2, 3, 4 or 5 substituents selectedfrom halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,OR^(a4), SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), and Cy³,wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl are optionallysubstituted with 1, 2, or 3 substituents independently selected fromhalo, OR^(a4) and Cy³; and

Cy³ is selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl,each optionally substituted with 1, 2, 3, 4 or 5 substituents selectedfrom halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, aryl,heteroaryl, CN, NO₂, NR^(c6)R^(d6), OR^(a6), and SR^(a6).

In some embodiments, the compounds of the invention have Formula IV,wherein R^(3a) is C₁₋₆ alkyl or C₁₋₆ haloalkyl, wherein said C₁₋₆ alkylis optionally substituted with 1, 2, or 3 substitutents independentlyselected from C(O)NR^(c)R^(d), C(O)OR^(a), NR^(c)R^(d),NR^(c)C(O)NR^(c)R^(d), and NR^(c)C(O)R^(b).

In some embodiments, the compounds of the invention have Formula IV,wherein R^(3a):

R^(3a) is selected from C₁₋₃ alkyl, wherein said C₁₋₃ alkyl issubstituted with Cy¹ and optionally substituted with 1 or 2substitutents independently selected from halo, OR^(a), and SR^(a);

Cy¹ is selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl,each substituted with 1 or 2 R⁷ and optionally substituted by 1, 2, or 3R⁸;

R⁷ is, at each occurrence, independently selected from Cy³ and C₁₋₄alkyl, wherein said C₁₋₄ alkyl is substituted with 1 or 2 Cy³ andoptionally substituted with 1 or 2 substitutents independently selectedfrom halo and OR^(a4);

R⁸ is, at each occurrence, independently selected from halo, C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, CN, NO₂, OR^(a4), SR^(a4),C(O)R^(b4), C(O)NR^(c4)R^(d4), and C(O)OR^(a4); and

Cy³ is selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl,each optionally substituted with 1, 2, 3, 4 or 5 substituents selectedfrom halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, aryl,heteroaryl, CN, NO₂, NR^(c6)R^(d6), OR^(a6), and SR^(a6).

At various places in the present specification, substituents ofcompounds of the invention are disclosed in groups or in ranges. It isspecifically intended that the invention include each and everyindividual subcombination of the members of such groups and ranges. Forexample, the term “C₁₋₆ alkyl” is specifically intended to individuallydisclose methyl, ethyl, C₃ alkyl (e.g., n-propyl or isopropyl), C₄ alkyl(e.g., n-butyl, isobutyl, t-butyl), or, C₅ alkyl (e.g., n-pentyl,isopentyl, or neopentyl), and C₆ alkyl.

For compounds of the invention in which a variable appears more thanonce, each variable can be a different moiety selected from the Markushgroup defining the variable. For example, where a structure is describedhaving two R groups that are simultaneously present on the samecompound; the two R groups can represent different moieties selectedfrom the Markush group defined for R. In another example, when anoptionally multiple substituent is designated in the form:

then it is understood that substituent R can occur s number of times onthe ring, and R can be a different moiety at each occurrence. Further,in the above example, should the variable T be defined to includehydrogens, such as when T is said to be CH₂, NH, etc., any floatingsubstituent such as R in the above example, can replace a hydrogen ofthe T variable as well as a hydrogen in any other non-variable componentof the ring.

It is further intended that the compounds of the invention are stable.As used herein “stable” refers to a compound that is sufficiently robustto survive isolation to a useful degree of purity from a reactionmixture, and preferably capable of formulation into an efficacioustherapeutic agent.

It is further appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment. Conversely,various features of the invention which are, for brevity, described inthe context of a single embodiment, can also be provided separately orin any suitable subcombination.

For compounds of the invention in which a variable appears more thanonce, each variable can be a different moiety selected from the Markushgroup defining the variable. For example, where a structure is describedhaving two R groups that are simultaneously present on the samecompound; the two R groups can represent different moieties selectedfrom the Markush group defined for R. As used herein, the term “alkyl”is meant to refer to a saturated hydrocarbon group which isstraight-chained or branched. Example alkyl groups include methyl (Me),ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl,isobutyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), andthe like. An alkyl group can contain from 1 to about 20, from 2 to about20, from 1 to about 10, from 1 to about 8, from 1 to about 6, from 1 toabout 4, or from 1 to about 3 carbon atoms.

As used herein, the term “alkylene” refers to a linking alkyl group. Oneexample of alkylene is CH₂CH₂.

As used herein, “alkenyl” refers to an alkyl group having one or moredouble carbon-carbon bonds. Example alkenyl groups include ethenyl,propenyl, and the like.

As used herein, “alkynyl” refers to an alkyl group having one or moretriple carbon-carbon bonds. Example alkynyl groups include ethynyl,propynyl, and the like.

As used herein, “haloalkyl” refers to an alkyl group having one or morehalogen substituents. Example haloalkyl groups include CH₂F, CHF₂, CF₃,C₂F₅, CCl₃, CHCl₂, CH₂CF₃, C₂Cl₅, and the like.

As used herein, “aryl” refers to monocyclic or polycyclic (e.g., having2, 3 or 4 fused rings) aromatic hydrocarbons such as, for example,phenyl, naphthyl, anthracenyl, phenanthrenyl, and the like. In someembodiments, aryl groups have from 6 to about 20 carbon atoms.

As used herein, “cycloalkyl” refers to non-aromatic carbocyclesincluding cyclized alkyl, alkenyl, and alkynyl groups. Cycloalkyl groupscan include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings)ring systems, including spirocycles. In some embodiments, cycloalkylgroups can have from 3 to about 20 carbon atoms, 3 to about 14 carbonatoms, 3 to about 10 carbon atoms, or 3 to 7 carbon atoms. Cycloalkylgroups can further have 0, 1, 2, or 3 double bonds and/or 0, 1, or 2triple bonds. Also included in the definition of cycloalkyl are moietiesthat have one or more aromatic rings fused (i.e., having a bond incommon with) to the cycloalkyl ring, for example, benzo derivatives ofpentane, pentene, hexane, and the like. A cycloalkyl group having one ormore fused aromatic rings can be attached though either the aromatic ornon-aromatic portion. One or more ring-forming carbon atoms of acycloalkyl group can be oxidized, for example, having an oxo or sulfidosubstituent. Example cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl,cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl,adamantyl, and the like.

As used herein, a “heteroaryl” group refers to an aromatic heterocyclehaving at least one heteroatom ring member such as sulfur, oxygen, ornitrogen. Heteroaryl groups include monocyclic and polycyclic (e.g.,having 2, 3 or 4 fused rings) systems. Any ring-forming N atom in aheteroaryl group can also be oxidized to form an N-oxo moiety. Examplesof heteroaryl groups include without limitation, pyridyl, N-oxopyridyl,pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl,isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl,benzofuryl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl,triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl,benzothienyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, and thelike. In some embodiments, the heteroaryl group has from 1 to about 20carbon atoms, and in further embodiments from about 3 to about 20 carbonatoms. In some embodiments, the heteroaryl group contains 3 to about 14,3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, theheteroaryl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms.

As used herein, “heterocycloalkyl” refers to a non-aromatic heterocyclewhere one or more of the ring-forming atoms is a heteroatom such as anO, N, or S atom. Heterocycloalkyl groups can include mono- or polycyclic(e.g., having 2, 3 or 4 fused rings) ring systems as well asspirocycles. Example “heterocycloalkyl” groups include morpholino,thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl,2,3-dihydrobenzofuryl, 1,3-benzodioxole, benzo-1,4-dioxane, piperidinyl,pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl,oxazolidinyl, thiazolidinyl, imidazolidinyl, and the like. Also includedin the definition of heterocycloalkyl are moieties that have one or morearomatic rings fused (i.e., having a bond in common with) to thenonaromatic heterocyclic ring, for example phthalimidyl, naphthalimidyl,and benzo derivatives of heterocycles. A heterocycloalkyl group havingone or more fused aromatic rings can be attached though either thearomatic or non-aromatic portion. In some embodiments, theheterocycloalkyl group has from 1 to about 20 carbon atoms, and infurther embodiments from about 3 to about 20 carbon atoms. In someembodiments, the heterocycloalkyl group contains 3 to about 20, 3 toabout 14, 3 to about 7, or 5 to 6 ring-forming atoms. In someembodiments, the heterocycloalkyl group has 1 to about 4, 1 to about 3,or 1 to 2 heteroatoms. In some embodiments, the heterocycloalkyl groupcontains 0 to 3 double bonds. In some embodiments, the heterocycloalkylgroup contains 0 to 2 triple bonds.

As used herein, “arylalkyl” refers to alkyl substituted by aryl and“cycloalkylalkyl” refers to alkyl substituted by cycloalkyl. One exampleof arylalkyl is benzyl. One example of cycloalkylalkyl is—CH₂CH₂-cyclopropyl.

As used herein, “heteroarylalkyl” refers to an alkyl group substitutedby a heteroaryl group, and “heterocycloalkylalkyl” refers to alkylsubstituted by heterocycloalkyl. One example of heteroarylalkyl is—CH₂-(pyridin-4-yl). One example of heterocycloalkylalkyl is—CH₂-(piperidin-3-yl).

As used herein, “halo” or “halogen” includes fluoro, chloro, bromo, andiodo.

As used herein, “hydroxyalkyl” refers to an alkyl group substituted witha hydroxyl group.

As used herein, “cyanoalkyl” refers to an alkyl group substituted with acyano group.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent invention that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically active starting materialsare known in the art, such as by resolution of racemic mixtures or bystereoselective synthesis. Many geometric isomers of olefins, C═N doublebonds, and the like can also be present in the compounds describedherein, and all such stable isomers are contemplated in the presentinvention. Cis and trans geometric isomers of the compounds of thepresent invention are described and may be isolated as a mixture ofisomers or as separated isomeric forms.

Compounds of the invention also include tautomeric forms. Tautomericforms result from the swapping of a single bond with an adjacent doublebond together with the concomitant migration of a proton. Tautomericforms include prototropic tautomers which are isomeric protonationstates having the same empirical formula and total charge. Exampleprototropic tautomers include ketone-enol pairs, amide-imidic acidpairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-iminepairs, and annular forms where a proton can occupy two or more positionsof a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H-and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole.Tautomeric forms can be in equilibrium or sterically locked into oneform by appropriate substitution.

Compounds of the invention can also include all isotopes of atomsoccurring in the intermediates or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.For example, isotopes of hydrogen include tritium and deuterium.

The term, “compound,” as used herein is meant to include allstereoisomers, geometric iosomers, tautomers, and isotopes of thestructures depicted.

All compounds, and pharmaceutically acceptable salts thereof, are alsomeant to include solvated or hydrated forms.

In some embodiments, the compounds of the invention, and salts thereof,are substantially isolated. By “substantially isolated” is meant thatthe compound is at least partially or substantially separated from theenvironment in which it was formed or detected. Partial separation caninclude, for example, a composition enriched in the compound of theinvention. Substantial separation can include compositions containing atleast about 50%, at least about 60%, at least about 70%, at least about80%, at least about 90%, at least about 95%, at least about 97%, or atleast about 99% by weight of the compound of the invention, or saltthereof. Methods for isolating compounds and their salts are routine inthe art.

The present invention also includes pharmaceutically acceptable salts ofthe compounds described herein. As used herein, “pharmaceuticallyacceptable salts” refers to derivatives of the disclosed compoundswherein the parent compound is modified by converting an existing acidor base moiety to its salt form. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidicresidues such as carboxylic acids; and the like. The pharmaceuticallyacceptable salts of the present invention include the conventionalnon-toxic salts of the parent compound formed, for example, fromnon-toxic inorganic or organic acids. The pharmaceutically acceptablesalts of the present invention can be synthesized from the parentcompound which contains a basic or acidic moiety by conventionalchemical methods. Generally, such salts can be prepared by reacting thefree acid or base forms of these compounds with a stoichiometric amountof the appropriate base or acid in water or in an organic solvent, or ina mixture of the two; generally, nonaqueous media like ether, ethylacetate, ethanol, isopropanol, or acetonitrile are preferred. Lists ofsuitable salts are found in Remington's Pharmaceutical Sciences, 17^(th)ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal ofPharmaceutical Science, 66, 2 (1977), each of which is incorporatedherein by reference in its entirety.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgement, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The present invention also includes prodrugs of the compounds describedherein. As used herein, “prodrugs” refer to any covalently bondedcarriers which release the active parent drug when administered to amammalian subject. Prodrugs can be prepared by modifying functionalgroups present in the compounds in such a way that the modifications arecleaved, either in routine manipulation or in vivo, to the parentcompounds. Prodrugs include compounds wherein hydroxyl, amino,sulfhydryl, or carboxyl groups are bonded to any group that, whenadministered to a mammalian subject, cleaves to form a free hydroxyl,amino, sulfhydryl, or carboxyl group respectively. Examples of prodrugsinclude, but are not limited to, acetate, formate and benzoatederivatives of alcohol and amine functional groups in the compounds ofthe invention. Preparation and use of prodrugs is discussed in T.Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 ofthe A.C.S. Symposium Series, and in Bioreversible Carriers in DrugDesign, ed. Edward B. Roche, American Pharmaceutical Association andPergamon Press, 1987, both of which are hereby incorporated by referencein their entirety.

Synthesis

The compounds of the present invention can be prepared in a variety ofways known to one skilled in the art of organic synthesis. The compoundsof the present invention can be synthesized using the methods ashereinafter described below, together with synthetic methods known inthe art of synthetic organic chemistry or variations thereon asappreciated by those skilled in the art.

The compounds of this invention can be prepared from readily availablestarting materials using the following general methods and procedures.It will be appreciated that where typical or preferred processconditions (i.e., reaction temperatures, times, mole ratios ofreactants, solvents, pressures, etc.) are given; other processconditions can also be used unless otherwise stated. Optimum reactionconditions may vary with the particular reactants or solvent used, butsuch conditions can be determined by one skilled in the art by routineoptimization procedures.

The processes described herein can be monitored according to anysuitable method known in the art. For example, product formation can bemonitored by spectroscopic means, such as nuclear magnetic resonancespectroscopy (e.g., ¹H or ¹³C) infrared spectroscopy, spectrophotometry(e.g., UV-visible), or mass spectrometry, or by chromatography such ashigh performance liquid chromatograpy (HPLC) or thin layerchromatography.

Preparation of compounds can involve the protection and deprotection ofvarious chemical groups. The need for protection and deprotection, andthe selection of appropriate protecting groups can be readily determinedby one skilled in the art. The chemistry of protecting groups can befound, for example, in Greene, et al., Protective Groups in OrganicSynthesis, 2d. Ed., Wiley & Sons, 1991, which is incorporated herein byreference in its entirety.

The reactions of the processes described herein can be carried out insuitable solvents which can be readily selected by one of skill in theart of organic synthesis. Suitable solvents can be substantiallynonreactive with the starting materials (reactants), the intermediates,or products at the temperatures at which the reactions are carried out,i.e., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected.

The compounds of the invention can be prepared, for example, using thereaction pathways and techniques as described below.

Compounds of formula 1i and 1j can be prepared using the generallyprotocol described in Scheme 1. Intermediates 1c can be synthesized byreaction of thiourea 1a with a cyanoacetic acid ester such as ethylcyanoacetate 1b in the present of a base such as sodium ethoxide togenerate cyclic intermediates 1c. Nitrosation of intermediate 1c usingsodium nitrite gives rise to the nitroso intermediate 1d, which can bereduced to the diamino intermediate 1e using Na₂S₂O₄ or a similarreducing agent. Cyclization of the diamino intermediate 1e withtrifluoroacetic anhydride yields the thioxopurinone intermediate 1f.Following selective methylation on the sulfur of compound 1f, theresulting thioether intermediate 1 g is subjected to a displacement withhydrazine to produce the hydrazone intermediate 1 h. Treatment of thehydrazone intermediate 1 h with an orthoester [such asR^(3b)C(O-alkyl)₃, e.g., R^(3b)C(OEt)₃] yields the cyclized triazolecompounds of formula 1i. Alternatively, intermediate 1 h can be treatedwith NaNO₂ to provide a cyclized tetrazole compound of formula 1j.

Compounds of formula 2 g and 2i can be prepared using the proceduresoutlined in Scheme 2. Selective alkylation at the amino group ofcommercially available 3-amino-1H-pyrrole-2-carboxamide (2a) byreductive amination with an aldehyde R¹L¹-CHO [wherein L¹-CH₂ has thesame definition as that of L defined hereinwith] provides the alkylatedproduct 2b. Reaction of intermediate 2b with benzoyl isothiocyanateyields the thiourea intermediate 2c, which can be treated with a basesuch as aqueous NaOH to provide the cyclized thioxopurinone intermediate2d. Treatment of intermediate 2d with aqueous hydrazine produces thehydrazone derivative 2e. Cyclization of the hydrazone intermediate 2ecan be achieved by treatment with an orthoester [such asR^(3b)C(O-alkyl)₃, e.g., R^(3b)C(OEt)₃] to yield the triazole derivative2f. Selective halogenation at the 7-position of 2f can be carried outusing a halogenating reagent, for example, N-bromosuccinimide (NBS) orN-chlorosuccinimide (NCS) to provide the halo-substitutedtriazolopurinone derivative of formula 2 g. Alternatively, thetetrazolopurinone derivatives of formula 2i can be obtained bycyclization of the intermediate 2e using NaNO₂ under acidic condition[such as in the presence of aqueous HCl] followed by halogenation usinga halogenating reagent, for example, NBS or NCS.

Compounds of formula 3d can be prepared using the protocol outlined inScheme 3. Reaction of hydrazone derivative 2e with an appropriatealdehyde R^(3b)CHO in a suitable solvent such as an alcohol (e.g.ethanol) yields intermediate 3b. Oxidative cyclization of 3b in aceticacid (in air) provides the corresponding triazolopurine 3c.Alternatively, triazolopurine 3c can be prepared by cyclization (andcondensation) of the intermediate 3f, which is derived from the amidebond formation by coupling of hydrazone 2e with acid 3e, in a suitablesolvent such as acetic acid or in toluene. Selective halogenation at the7-position of the triazolopurinone core of 3c using a halogenationreagent, for example NBS or NCS, provides the halo-substitutedtriazolopurinone derivative of formula 3d.

Compounds of formula 4f and 4j [wherein R⁷ can be aryl, heteroaryl,arylakyl, heteroarylalkyl, and the like] can be prepared using theprocedures described in Scheme 4. Oxidative cyclization of hydrazone 4b,which is generated from treatment of hydrazone 2e with an aldehyde 4a ina suitable solvent such as ethanol, provides the intermediate acid 4c.Reaction of acid 4c with amine 4d under amide formation condition [suchas in the presence of an amide coupling reagent, for example,benzotriazolyloy-tris-(dimethylamino)phosphonium hexafluorophosphate (orBOP)] produces amide 4e, which can be treated with a halogenatingreagent such as NBS or NCS to provide a halo-substitutedtriazolopurinone amide derivative of formula 4f. Oxadiazol intermediate4i can be prepared by coupling of acid 4c with N-hydroxy imidamide 4 gusing a coupling reagent such as 1,1′-carbonyldiimidazole (CDI),followed by cyclization (and condensation). Alternatively, coupling ofoxadiazol acid 4 h with hydrazone 2e under suitable conditions (such asin the presence of an amid coupling reagent, for example BOP), followedby cyclization (and condensation), can also yield oxadiazole 4i.Selective halogenation at the 7-position of the triazolopurinone core ofcompound 4i, using a halogenating reagent such as NBS or NCS, providesthe halo-substituted triazolopurinone oxadiazol derivative of formula4j.

Compounds of formula 5b can be synthesized using the general proceduresoutlined in Scheme 5. Reaction of halide 3d with a boric acid 5a (suchas those commercially available or disclosed in the literatures, whereinZ is optionally substituted aryl or optionally substituted heteraryl)under Suzuki coupling conditions can yield triazolopurinone derivativesof formula 5b.

An alternative general synthetic pathway for 5b starts with intermediate1e. Reaction of intermediate 1e with acid 5c (wherein Z can beoptionally substituted aryl, heteroaryl, cycloalkyl, orheterocycloalkyl) under amide coupling conditions (such as in thepresence of an amid coupling reagent, for example BOP) provides amide5d, which can be treated with a base such as aqueous NaOH to givethioxopurinone intermediate 5e. Treatment of intermediate 5e withaqueous hydrazine produces the hydrazone derivative 5f. Reaction ofdyazone 5f with an orthoester [such as R^(3b)C(O-alkyl)₃, e.g.,R^(3b)C(OEt)₃] yields triazolopurinone derivative 5b.

Alternatively, halide 3d can be reacted with an alkyne 5 g underSonogashira coupling condition to afford an allyne derivative 5 h. (See,e.g., Sonogashira, K. et al. Tetrahedron Letter, 1975, 4467; see also,Nicolaou, K. C. Et al. Angew. Chem. Int. Engl. 1991, 30, 1100)

Scheme 6 exemplifies the preparation of 3-substituted triazolopurinonederivatives such as those having formula 6d, 6 g or 6j. Treatment ofhydrazone 2e with N-(dichloromethylene)-N-methylmethananaminium chlorideprovide 6c, which can be treated with a halogenated reagent such as NBSor NCS to yield halo-substituted amino triazolopurinone derivative 6d.Reaction of 2e with carbon disulfide in a suitable solvent such aspyridine produces cyclic thiourea 6e. Alkylation of thiourea 6e on thesulfur atom using an appropriate alkylating agent such as dimethylsulfate or ethyl iodide under basic condition (such as in the presenceof aqueous NaOH), followed by oxidation of the resultant thioether inthe presence of an oxidizing reagent such as m-chloroperbenzoic acid,affords sulfinyl intermediate 6f, which can be treated with ahalogenating reagent such as NBS or NCS to provide halo-substitutedsulfinyl-triazolopurinone derivative 6 g. Sulfinyl intermediate 6f (orits precursor thioether) can be further oxidized to its correspondingsulfonyl counterpart, which in turn can further undergo selectivehalogenation. Treatment of hydrazone 2e with CDI give intermediates 6 h.Alkylation of intermediate 6 h on the hydroxyl group (such as usingalkyl halide R^(a)X¹ wherein X¹ is bromo), followed by halogenation witha halogenating reagent such as NBS or NCS, provides triazolopurinonederivatives of formula 6j.

Compounds of formula 4j can be also prepared using the proceduresdescribed in Scheme 7. Reaction of hydrazone 2e with cyclic anhydride 7a(wherein n can be 1, 2 or 3) under suitable conditions (such asrefluxing in dioxane) furnishes triazolopurinone acid derivative 7b.Selective halogenation at the 7-position of the triazolopurinone core ofcompound 7b using a halogenating reagent such as NBS or NCS provides thehalo-substituted triazolopurinone derivative 7c. Coupling of acid 7cwith N-hydroxy imidamide 4 g [wherein R⁷ can be aryl, heteroaryl,arylakyl, heteroarylalkyl, and the like] using a coupling reagent suchas CDI, followed by cyclization (and condensation), yieldshalo-substituted triazolopurinone oxadiazol derivative 4j.

Compounds of formula 8f (wherein ring A¹ is a heterocylic ring that hasat least one nitrogen atom as ring-forming atom and that is substitutedby R⁷ and optionally substituted by one or more R⁸ wherein R⁷ can bearyl, heteroaryl, arylakyl, heteroarylalkyl, and the like; R⁸ can bealkyl, haloalkyl, alkoxy and the like; and t can be 0, 1, 2 or 3) can beprepared using the protocol outlined in Scheme 8. Reacting of anNH-containing heterocycle 8a (which is substituted by R⁷ and optionallysubstituted by 1, 2 or 3 R⁸) with halo-substituted ester 8b (wherein ncan be 1, or 2) in the presence of a base such as K₂CO₃ gives ester 8c.Hydrolysis of ester 8c under basic conditions (such as using sodiumhydroxide in water-methanol) provides acid 8d. Coupling of acid 8d withhydrazone 2e, followed by cyclization (and condensation), affordstrazolopurinone derivative 8e, which is subjected to selectivehalogenation to yield the halo-substituted trazolopurinone derivativeformula 8f.

Compounds of formula 9 h can be prepared using the general proceduresdescribed in Scheme 9. Addition of hydroxylamine to commerciallyavailable 4,4-diethoxybutanenitrile 9a (wherein n can be 1, or 2) inmethanol provide imidamide 9b. Coupling of imidamide 9b with acid 9c(wherein R⁷ can be aryl, heteroaryl, arylakyl, heteroarylalkyl, and thelike) in the presence of a coupling reagent such as CDI, followed bycyclization (and condensation), affords oxadiazole derivative 9d, whichcan undergo acid catalyzed ketal deprotection to furnish oxadiazolealdehyde 9e. Reaction of aldehyde 9e with hydrazone derivative 2e in asuitable solvent such as ethanol provides intermediate 9f. Oxidativecyclization of 9f (such as in acetic acid and in the presence of air)provides the corresponding triazolopurine 9 g, which can be treated witha halogenating reagent NBS or NCS to yield halo-substitutedtriazolopurinone oxadiazol derivative 9 h.

Compounds of formula 10e, 10f or 10 g can be prepared using the protocoldescribed in Scheme 10. Amide coupling of protected amino acid 10a[wherein P¹ is an amine protecting group such as tert-butyloxycarbonyl(or Boc) or benzyloxycarbonyl (or Cbz); and n can be 1, or 2] withhydrazone 2e gives intermediate amide 10b. Cyclization of 10b undersuitable conditions such as refluxing in acetic acid or refluxing intoluene, followed by deprotection of the amino group (that has theprotecting group P¹), provides amino-substituted triazolopurinonederivative 10c. Selective halogenation at the 7-position of thetriazolopurinone core of compound 10c using a halogenating reagent, forexample, NBS or NCS provides intermediate 10d. Amide coupling ofintermediate 10d with acid R^(b)—COOH (wherein R^(b) can be, forexample, aryl, heteroaryl, arylakyl, heteroarylalkyl, and the like)yields halo-substituted triazolopurinone amide derivative 10e.Triazolopurinone urea derivative 10f can be obtained by reactingintermediate 10d with an isocyanate R^(d)—N═C═O or its equivalent [suchas a carbamate, for example R^(d)—NH—(C═O)—O-akyl (e.g.,R^(d)—NH—(C═O)—O-methyl) or R^(d)—NH—(C═O)—O-phenyl]. Reaction ofintermediate 10d with R^(d)—X² wherein X² is a leaving group such ashalide [R^(d)—X can be aryl halide or heteroaryl halide] underbase-facilitated nucleophilic replacement condition or palladiumcatalyzed arylamination condition provides halo-substitutedtriazolopurinone derivatives of formula 10 g.

Pharmaceutical Methods

Compounds of the invention can modulate activity of the HM74a receptor.The term “modulate” is meant to refer to an ability to increase ordecrease activity of a receptor. Accordingly, compounds of the inventioncan be used in methods of modulating HM74a receptor by contacting thereceptor with any one or more of the compounds or compositions describedherein. In some embodiments, compounds of the present invention can actas full or partial agonists of HM74a receptors. In further embodiments,the compounds of the invention can be used to modulate activity of HM74areceptors in an individual by administering a modulating amount of acompound of the invention.

The present invention further provides methods of treating diseasesassociated with the HM74a receptor, such as dyslipidemia, insulinresistance, hyperglycemia, and others, in an individual (e.g., patient)by administering to the individual in need of such treatment atherapeutically effective amount or dose of a compound of the presentinvention or a pharmaceutical composition thereof. Example diseases caninclude any disease, disorder or condition that is directly orindirectly linked to the HM74a receptor, such as diseases, disorders orconditions associated with low expression or low activity of HM74areceptor.

Examples of HM74a receptor-associated diseases include, but are notlimited to, dyslipidemia, highly-active anti-retroviral therapy(HAART)-associated lipodystrophy, insulin resistance, diabetes such astype 2 diabetes mellitus, metabolic syndrome, atherosclerosis, coronaryheart disease, stroke, obesity, elevated body mass index (BMI), elevatedwaist circumference, non-alcoholic fatty liver disease, hepaticsteatosis, hypertension, and other pathologies, such as those (like manyof the aforementioned) associated with elevated plasma FFAs.

Other diseases treatable by administration of compounds of the invention(and salts or prodrugs there) include chronic inflammatory diseases suchas, for example, pancreatitis and gout.

As used herein, the term “dyslipidemia” refers to any one or more of thefollowing diseases or conditions: low-HDL cholesterol, elevatedcholesterol, elevated LDL cholesterol (including any combination ofsmall, dense LDL, intermediate density lipoproteins, very-low densitylipoproteins, and chylomicrons), elevated total cholesterol/HDL ratio,elevated plasma triglycerides, elevated circulating free fatty acidlevels, and elevated lipoprotein (a).

In some embodiments, the present invention provides methods of loweringcholesterol level, lowering LDL, lowering total cholesterol/HDL ratio,lowering plasma triglycerides, lowering circulating free fatty acidlevels, lowering lipoprotein (a), or raising HDL cholesterol, in amammal by administering an effective amount of a compound or compositionherein to the mammal.

As used herein, the term “cell” is meant to refer to a cell that is invitro, ex vivo or in vivo. In some embodiments, an ex vivo cell can bepart of a tissue sample excised from an organism such as a mammal. Insome embodiments, an in vitro cell can be a cell in a cell culture. Insome embodiments, an in vivo cell is a cell living in an organism suchas a mammal. In some embodiments, the cell is an adipocyte, a pancreaticcell, a hepatocyte, neuron, or cell comprising the eye.

As used herein, the term “contacting” refers to the bringing together ofindicated moieties in an in vitro system or an in vivo system. Forexample, “contacting” the HM74a receptor with a compound of theinvention includes the administration of a compound of the presentinvention to an individual or patient, such as a human, having the HM74areceptor, as well as, for example, introducing a compound of theinvention into a sample containing a cellular or purified preparationcontaining the HM74a receptor.

As used herein, the term “individual” or “patient,” usedinterchangeably, refers to any animal, including mammals, preferablymice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep,horses, or primates, and most preferably humans.

As used herein, the phrase “therapeutically effective amount” refers tothe amount of active compound or pharmaceutical agent that elicits thebiological or medicinal response that is being sought in a tissue,system, animal, individual or human by a researcher, veterinarian,medical doctor or other clinician.

As used herein, the term “treating” or “treatment” refers to one or moreof (1) preventing the disease; for example, preventing a disease,condition or disorder in an individual who may be predisposed to thedisease, condition or disorder but does not yet experience or displaythe pathology or symptomatology of the disease; (2) inhibiting thedisease; for example, inhibiting a disease, condition or disorder in anindividual who is experiencing or displaying the pathology orsymptomatology of the disease, condition or disorder; and (3)ameliorating the disease; for example, ameliorating a disease, conditionor disorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,reversing or retarding the pathology and/or symptomatology) such asdecreasing the severity of disease.

Combination Therapies

The compounds of the present invention can be used in combination withother enzyme or receptor modulators. Examples of other enzyme orreceptor modulators include, but are not limited to, any one or more ofthe following: steroidal and non-steroidal anti-inflammatory agents(e.g., inhibitors or prostaglandin synthesis), inhibitors of PCSK9,inhibitors of ACC1, inhibitors of ACC2, inhibitors of SCD1, inhibitorsof DGAT, activators of AMPK, thyroid receptor modulators, renininhibitors, agents that degrade or inhibit formation of advancedglycation end products, HMG-CoA reductase inhibitors (so-calledstatins), PPAR alpha agonists or selective modulators, PPAR gammaagonists or selective modulators (both TZD and non-TZD), PPAR deltaagonists or selective modulators, PPAR alpha/gamma dual agonists,pan-PPAR agonists or selective modulators, glucocorticoid receptorantagonists or selective modulators, bile acid-binding resins, NPC1L1receptor antagonists, cholesterol ester transfer protein inhibitors,apoA-I or synthetic apoA-I/HDL molecules, LXR agonists or selectivemodulators, FXR agonists or selective modulators, endothelial lipaseinhibitors, hepatic lipase inhibitors, SR-BI modulators, estrogenreceptor agonists or selective modulators, anabolic steroid or steroidderivatives, insulin or insulin mimetics, sulfonylureas, metformin orother biguanides, DPP-IV inhibitors, PTP-1B modulators,glucose-6-phosphatase inhibitors, T1-translocase inhibitors,fructose-1,6-bisphosphatase inhibitors, glycogen phosphorylaseinhibitors, glucagon receptor antagonists, 11-beta-hydroxysteroiddehydrogenase type 1 inhibitors, intestinal lipase inhibitors,neurotransmitter reuptake inhibitor, endocannabinoid receptorantagonist, NPY antagonist, MCH antagonists, MC4R agonists, GLP-1 orGLP-1 analogues (incretins), GLP-1 receptor agonists, thiazidediuretics, beta-adrenergic receptor antagonists, angiotensin IIconverting enzyme inhibitors, angiotensin II receptor antagonists,calcium channel antagonists, and mineralocorticoid receptor antagonists,or combinations thereof.

Pharmaceutical Formulations and Dosage Forms

When employed as pharmaceuticals, the compounds of the invention can beadministered in the form of pharmaceutical compositions. Thesecompositions can be prepared in a manner well known in thepharmaceutical art, and can be administered by a variety of routes,depending upon whether local or systemic treatment is desired and uponthe area to be treated. Administration may be topical (includingophthalmic and to mucous membranes including intranasal, vaginal andrectal delivery), pulmonary (e.g., by inhalation or insufflation ofpowders or aerosols, including by nebulizer; intratracheal, intranasal,epidermal and transdermal), ocular, oral or parenteral. Methods forocular delivery can include topical administration (eye drops),subconjunctival, periocular or intravitreal injection or introduction byballoon catheter or ophthalmic inserts surgically placed in theconjunctival sac. Parenteral administration includes intravenous,intraarterial, subcutaneous, intraperitoneal or intramuscular injectionor infusion; or intracranial, e.g., intrathecal or intraventricular,administration. Parenteral administration can be in the form of a singlebolus dose, or may be, for example, by a continuous perfusion pump.Pharmaceutical compositions and formulations for topical administrationmay include transdermal patches, ointments, lotions, creams, gels,drops, suppositories, sprays, liquids and powders. Conventionalpharmaceutical carriers, aqueous, powder or oily bases, thickeners andthe like may be necessary or desirable.

This invention also includes pharmaceutical compositions which contain,as the active ingredient, one or more of the compounds of the inventionabove in combination with one or more pharmaceutically acceptablecarriers. In making the compositions of the invention, the activeingredient is typically mixed with an excipient, diluted by an excipientor enclosed within such a carrier in the form of, for example, acapsule, sachet, paper, or other container. When the excipient serves asa diluent, it can be a solid, semi-solid, or liquid material, which actsas a vehicle, carrier or medium for the active ingredient. Thus, thecompositions can be in the form of tablets, pills, powders, lozenges,sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups,aerosols (as a solid or in a liquid medium), ointments containing, forexample, up to 10% by weight of the active compound, soft and hardgelatin capsules, suppositories, sterile injectable solutions, andsterile packaged powders.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g. about 40 mesh.

The compounds of the invention may be milled using known millingprocedures such as wet milling to obtain a particle size appropriate fortablet formation and for other formulation types. Finely divided(nanoparticulate) preparations of the compounds of the invention can beprepared by processes known in the art, for example see InternationalPatent Application No. WO 2002/000196.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 100 mg, more usually about 10 to about30 mg, of the active ingredient. The term “unit dosage forms” refers tophysically discrete units suitable as unitary dosages for human subjectsand other mammals, each unit containing a predetermined quantity ofactive material calculated to produce the desired therapeutic effect, inassociation with a suitable pharmaceutical excipient.

The active compound can be effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It willbe understood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, the active ingredient istypically dispersed evenly throughout the composition so that thecomposition can be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, for example, 0.1 to about 500 mg of the activeingredient of the present invention.

The tablets or pills of the present invention can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

The liquid forms in which the compounds and compositions of the presentinvention can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions in can be nebulized by use of inert gases. Nebulizedsolutions may be breathed directly from the nebulizing device or thenebulizing device can be attached to a face masks tent, or intermittentpositive pressure breathing machine. Solution, suspension, or powdercompositions can be administered orally or nasally from devices whichdeliver the formulation in an appropriate manner.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration, and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient, and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers, or stabilizers willresult in the formation of pharmaceutical salts.

The therapeutic dosage of the compounds of the present invention canvary according to, for example, the particular use for which thetreatment is made, the manner of administration of the compound, thehealth and condition of the patient, and the judgment of the prescribingphysician. The proportion or concentration of a compound of theinvention in a pharmaceutical composition can vary depending upon anumber of factors including dosage, chemical characteristics (e.g.,hydrophobicity), and the route of administration. For example, thecompounds of the invention can be provided in an aqueous physiologicalbuffer solution containing about 0.1 to about 10% w/v of the compoundfor parenteral administration. Some typical dose ranges are from about 1μg/kg to about 1 g/kg of body weight per day. In some embodiments, thedose range is from about 0.01 mg/kg to about 100 mg/kg of body weightper day. The dosage is likely to depend on such variables as the typeand extent of progression of the disease or disorder, the overall healthstatus of the particular patient, the relative biological efficacy ofthe compound selected, formulation of the excipient, and its route ofadministration. Effective doses can be extrapolated from dose-responsecurves derived from in vitro or animal model test systems.

The compounds of the invention can also be formulated in combinationwith one or more additional active ingredients which can include anypharmaceutical agent such as anti-viral agents, antibodies, immunesuppressants, anti-inflammatory agents and the like.

Labeled Compounds and Assay Methods

Another aspect of the present invention relates to fluorescent dye, spintable, heavy metal or radio-labeled compounds of the invention thatwould be useful not only in imaging but also in assays, both in vitroand in vivo, for localizing and quantitating HM74a in tissue samples,including human, and for identifying HM74a ligands by binding of alabeled compound. Accordingly, the present invention includes HM74aassays that contain such labeled compounds.

The present invention further includes isotopically-labeled compounds ofthe invention. An “isotopically” or “radio-labeled” compound is acompound of the invention where one or more atoms are replaced orsubstituted by an atom having an atomic mass or mass number differentfrom the atomic mass or mass number typically found in nature (i.e.,naturally occurring). Suitable radionuclides that may be incorporated incompounds of the present invention include but are not limited to ²H(also written as D for deuterium), ³H (also written as T for tritium),¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br,⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I. The radionuclide that isincorporated in the instant radio-labeled compounds will depend on thespecific application of that radio-labeled compound. For example, for invitro labeling and competition assays, compounds that incorporate ³H,¹⁴C, ⁸²Br, ¹²⁵I, ¹³¹I, ³⁵S or will generally be most useful. Forradio-imaging applications ¹¹C, ¹⁸F, ¹²⁵I, ¹²³I, ¹²⁴I, ¹³¹I, ⁷⁵Br, ⁷⁸Bror ⁷⁷Br will generally be most useful.

It is understood that a “radio-labeled” or “labeled compound” is acompound that has incorporated at least one radionuclide. In someembodiments the radionuclide is selected from the group consisting of³H, ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br.

Synthetic methods for incorporating radio-isotopes into organiccompounds are applicable to compounds of the invention and are wellknown in the art.

A radio-labeled compound of the invention can be used in a screeningassay to identify/evaluate compounds. In general terms, a newlysynthesized or identified compound (i.e., test compound) can beevaluated for its ability to reduce binding of the radio-labeledcompound of the invention to HM74a. Accordingly, the ability of a testcompound to compete with the radio-labeled compound for binding to HM74adirectly correlates to its binding affinity.

Kits

The present invention also includes pharmaceutical kits useful, forexample, in the treatment or prevention of HM74a-associated diseases ordisorders. The kits can include one or more containers containing apharmaceutical composition comprising a therapeutically effective amountof a compound of the invention. Such kits can further include, ifdesired, one or more of various conventional pharmaceutical kitcomponents, such as, for example, containers with one or morepharmaceutically acceptable carriers, additional containers, etc., aswill be readily apparent to those skilled in the art. Instructions,either as inserts or as labels, indicating quantities of the componentsto be administered, guidelines for administration, and/or guidelines formixing the components, can also be included in the kit.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of noncriticalparameters which can be changed or modified to yield essentially thesame results.

The compounds of the example section were found to be agonists orpartial agonists of HM74a receptor according to one or more of theassays provided herein.

EXAMPLES General Information

All reagents and solvents were obtained from commercial sources and wereused directly without further purification. LCMS analysis was performedon a Water SunFire C18 column ((2.1×50 mm, 5 μM particle size), elutingwith 0.025% TFA/water and 0.025% TFA/acetonitrile using a mass spectrumscan range of 105-900 Da. Preparative LCMS purifications were performedon a Water FractionLynx system using mass directed fraction andcompound-specific method optimization (J. Comb. Chem. 2004, 6, 874-883).The LC method utilized a Water SunFire column (19×100 mm, 5 μM particlesize), eluting with either 0.1% TFA/water and 0.1% TFA/acetonitrilegradient at a flow rate of 30 mL/min over a total run time of 5 min NMRspectra were obtained using a Varian Mercury-300 or Mercury-400spectrometer. Chemical shifts are reported in parts per million (ppm)relative to tetramethylsilane as an internal standard.

Example 1 Preparation of3-methyl-9-pentyl-7-(trifluoromethyl)-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

Step A: N-Pentylthiourea

Pentylisothiocyanate (10 g, 0.08 mol) was added slowly (about 10 mins)to a mixture of ammonia (50 mL, 0.2 mol) in methanol (7 N) at 0° C.After being stirred at room temperature for 1 h, the solvent wasstripped off and the product was obtained as a white solid (10 g,88.4%), which was used for next step without further purification. LCMScalculated for C₆H₁₅N₂S: (M+H) 147.1. found 147.1.

Step B: 6-Amino-1-pentyl-2-thioxo-2,3-dihydropyrimidin-4(1H)-one

N-Pentylthiourea (10.0 g, 0.068 mol) was mixed with ethyl cyanoacetate(9.3 g, 0.082 mol) and sodium ethoxide (6.4 g, 0.094 mol) in ethanol (60mL). The mixture was stirred at 75° C. overnight. After cooling, asolution of 10% acetic acid in water (150 mL) was added. The solidformed was collected by filtration and washed with water to afford thedesired product (9.5 g, 65% yield). LCMS calculated for C₉H₁₆N₃OS: (M+H)214.1. found 214.1.

Step C:6-Amino-5-nitroso-1-pentyl-2-thioxo-2,3-dihydropyrimidin-4(1H)-one

6-Amino-1-pentyl-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (8.0 g, 0.038mol) was mixed with sodium nitrite (3.1 g, 0.045 mol) in acetic acid(120 mL). The mixture was stirred at 75° C. for 1 h. The color of thereaction mixture became pink and then purple. The solution was allowedto cool down to room temperature, and water (40 mL) was added. The solidwas collected by suction filtration and washed with water (50 mL) toproduce the desired product, which was used directly for next stepwithout further purification. LCMS calculated for C₉H₁₅N₄O₂S: (M+H)243.1. found 243.1.

Step D: 5,6-Diamino-1-pentyl-2-thioxo-2,3-dihydropyrimidin-4(1H)-one

To a mixture of6-amino-1-pentyl-5-nitroso-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (6.4g, 0.0264 mol), aqueous ammonia (60 mL, 0.60 mol) and water (60 mL) at75° C. was added sodium dithionite (9.0 g, 0.050 mol) in small portions.After the addition was complete, the color of the solution changed fromred to pale yellow. After stirring at 75° C. for another 5 mins, aprecipitate was formed. Stirring was continued at room temperature for1.5 h. The solution was then neutralized with 10% acetic acid (150 mL).The solid was filtered and washed with water to yield the product (4.5g, 86.1%). LCMS calculated for C₉H₁₇N₄OS: (M+H) 229.1. found 229.1.

Step E:3-Pentyl-2-thioxo-8-(trifluoromethyl)-1,2,3,7-tetrahydro-6H-purin-6-one

5,6-Diamino-1-pentyl-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (2.0 g,0.0088 mol) was mixed with trifluoroacetic anhydride (10 mL, 0.07 mol).After stirring at 45° C. for 2 h, the excess trifluoroacetic anhydridewas removed at reduced pressure. The residue was dissolved inN,N-dimethylformamide (5 mL) and heated at 95° C. for 1 h. After coolingto room temperature, the reaction mixture was diluted with water andextracted with ethyl acetate. The combined organic layers were driedover anhydrous Na₂SO₄, filtered and concentrated. The solid residue waswashed with ether to provide the desired product (1.50 g, 55.9%). LCMScalculated for C₁₁H₁₄F₃N₄OS: (M+H) 307.1. found 307.1.

Step F:2-(Methylthio)-3-pentyl-8-(trifluoromethyl)-3,7-dihydro-6H-purin-6-one

To the solution of3-pentyl-2-thioxo-8-(trifluoromethyl)-1,2,3,7-tetrahydro-6H-purin-6-one(600 mg, 2 mmol) in a 2 M solution of sodium hydroxide in water (12.0mL) was added dimethyl sulfate (0.30 mL, 3.2 mmol). The reaction mixturewas stirred at room temperature for 1.5 h and quenched with acetic acid.The resulting solution was extracted with methylene chloride threetimes. The combined organic layer was dried, filtered and concentratedto give the desired product (0.60 g, 95.6%). LCMS calculated forC₁₂H₁₆F₃N₄OS: (M+H) 321.1. found 321.1.

Step G:(2E)-3-Pentyl-8-(trifluoromethyl)-3,7-dihydro-1H-purine-2,6-dione-2-hydrazone

A mixture of2-(methylthio)-3-pentyl-8-(trifluoromethyl)-1,2,3,7-tetrahydro-6H-purin-6-one(0.61 g, 0.95 mmol), hydrazine (3 mL, 100 mmol) and water (3 mL) wasstirred at 100° C. for 1 h. The reaction solution was concentrated underreduced pressure. The residue was dissolved in DMSO and purified bypreparative LCMS. The product fractions were collected and lyophilizedto give the desired product (0.25 g, 65%). LCMS calculated forC₁₁H₁₅F₃N₆O: (M+H) 305.1. found 305.1.

Step H:3-Methyl-9-pentyl-7-(trifluoromethyl)-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

A mixture of(2E)-3-pentyl-8-(trifluoromethyl)-3,7-dihydro-1H-purine-2,6-dione-2-hydrazone(0.020 g, 0.14 mmol) and triethyl orthoacetate (2 mL, 10 mmol) wasstirred at room temperature for 1 h. The reaction mixture wasconcentrated under vacuum and the residue was purified by preparativeLCMS. The product fractions were collected and lyophilized to yield pureproduct as white powder. LCMS calculated for C₁₃H₁₅F₃N₆O: (M+H) 329.1.found: 329.1.

Example 2 Preparation of9-butyl-3-methyl-7-(trifluoromethyl)-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 1. LCMS calculated for C₁₂H₁₃F₃N₆O: (M+H) 315.1.found 315.1.

Example 3 Preparation of9-pentyl-7-(trifluoromethyl)-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

A mixture of(2E)-3-pentyl-8-(trifluoromethyl)-3,7-dihydro-1H-purine-2,6-dione-2-hydrazone(0.020 g, 0.14 mmol) and triethyl orthoformate (2 mL, 0.01 mol) wasstirred at room temperature for 1 h. The reaction mixture wasconcentrated under vacuum and the residue was purified by preparativeLCMS. The product fractions were collected and lyophilized to yield pureproduct as white powder (0.1 g, 48%). LCMS calculated for C₁₂H₁₃F₃N₆O:(M+H) 315.1. found: 315.1.

Example 4 Preparation of9-butyl-7-(trifluoromethyl)-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 3. LCMS calculated for C₁₁H₁₁F₃N₆O: (M+H) 301.1.found 301.1.

Example 5 Preparation of7-bromo-3-methyl-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

Step A: 4-(Pentylamino)-1H-imidazole-5-carboxamide

4-Amino-1H-imidazole-5-carboxamide (13.0 g, 0.104 mol) and valeraldehyde(11 mL, 0.10 mol) were mixed in methanol (200 mL). After being stirredfor 30 min, sodium cyanoborohydride (6.5 g, 0.10 mol) was added to thesolution and stirring was continued overnight. The reaction mixture wasconcentrated under reduced pressure. The remaining residue was taken upin EtOAc and the resulting solution was washed with saturated NaHCO₃.The aqueous layer was extracted with EtOAc three times. The combinedorganic layers were dried (MgSO₄) and concentrated. The residue waspurified by flash chromatography (DCM to 5% MeOH/DCM) to give thedesired product (12.9 g, 63.1%). LCMS calculated for C₉H₁₆N₄O (M+H):197.1. found: 180.1 (M+H—NH₃).

Step B:4-[[(Benzoylamino)carbonothioyl](pentyl)amino]-1H-imidazole-5-carboxamide

To a solution of 4-(pentylamino)-1H-imidazole-5-carboxamide (4.0 g,0.020 mol) in DCM (50 mL) was added benzoyl isothiocyanate (3.3 mL,0.024 mol). After being stirred overnight, the solid formed was filteredto give the crude product (10 g, ca 60% purity, 80% yield). This productwas used for next step without further purification. LCMS calculated forC₁₇H₂₂N₅O₂S (M+H): 360.1. found: 360.1.

Step C: 3-Pentyl-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one

A mixture of4-[[(benzoylamino)carbonothioyl](pentyl)amino]-1H-imidazole-5-carboxamide(11.8 g, 0.0263 mol) and 1 M of sodium hydroxide in water (75 mL) washeated to reflux for 3 h. Solid was formed in the reaction mixture. Thereaction mixture was adjusted to pH 3-4 with concentrated HCl withcooling in an ice bath. The solid was filtered, washed with water andair-dried to give the product (9.0 g, 65% purity, 94% yield). Theproduct was used for the next step without further purification. LCMScalculated for C₁₀H₁₅N₄OS (M+H): 239.1. found: 239.1.

Step D: (2E)-3-Pentyl-3,7-dihydro-1H-purine-2,6-dione 2-hydrazone

3-Pentyl-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one (6.0 g, 16 mmol) wasmixed with hydrazine (10 mL, 300 mmol) and water (10 mL). The mixturewas heated at 100° C. for 8 h. The solid formed was filtered and washedwith water to give the desired product (3.0 g, 78%). LCMS calculated forC₁₀H₁₇N₆O (M+H): 237.1. found: 237.1.

Step E:3-Methyl-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

A mixture of (2Z)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione 2-hydrazone(3.1 g, 0.013 mol) and triethyl orthoacetate (20 mL, 0.1 mol) was heatedat 100° C. for 3 h. The suspension was cooled to room temperature andthe solid formed was filtered and washed with DCM/Hex (1:1) mixture toprovide the desired product (3.1 g, 91% yield). LCMS calculated forC₁₂H₁₇N₆O (M+H): 261.1. found: 261.1.

Step F:7-Bromo-3-methyl-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

To a solution of3-methyl-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one (1.0g, 3.8 mmol) in THF (50 mL) was added N-bromosuccinimide (0.75 g, 4.2mol). The mixture was heated at 70° C. for 1 h and concentrated invacuum. The residue was taken up in water and EtOAc. The organic layerwas separated and the aqueous layer was extracted with ethyl acetatethree times.

The combined organic layers were dried (MgSO₄), filtered, andconcentrated in vacuum. The residue was purified by preparative LCMS toprovide the desired product as a white powder (0.4 g, 30% yield). ¹HNMR(400 MHz, d₆-DMSO): δ 4.18 (t, J=7.5 Hz, 2H), 2.71 (s, 3H), 1.79 (m,2H), 1.29 (m, 4H), 0.84 (m, 3H). LCMS calculated for C₁₂H₁₆BrN₆O (M+H):339.1, 341.1. found: 339.1, 341.1.

Example 6 Preparation of7-bromo-3-methyl-9-butyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 5. LCMS calculated for: C₁₁H₁₄BrN₆O (M+H) 325.1,327.1. found: 325.1, 327.1.

Example 7 Preparation of7-chloro-3-methyl-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

To a solution of3-methyl-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one (0.10g, 0.38 mmol) in THF (5 mL) in a microwave reaction tube was addedN-chlorosuccinimide (0.046 g, 0.42 mmol). The mixture was heated at 70°C. in a microwave oven for 20 min After cooling to room temperature, itwas purified using preparative LCMS to provide the product (0.021 g).¹HNMR (300 MHz, CD₃OD): δ 4.39 (t, J=7.5 Hz, 2H), 2.46 (s, 3H), 1.91 (m,2H), 1.39 (m, 4H), 0.92 (m, 3H). LCMS calculated for C₁₂H₁₆ClN₆O (M+H):295.1. found: 295.1.

Example 8 Preparation of7-chloro-3-methyl-9-butyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 7. LCMS calculated for: C₁₁H₁₄ClN₆O (M+H) 281.1.found: 281.1.

Example 97-bromo-3-(methylthio)-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

Step A:9-pentyl-3-thioxo-2,3,6,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

A solution of (2e)-3-pentyl-3,7-dihydro-1 h-purine-2,6-dione 2-hydrazone(1.90 g, 8.04 mmol) and carbon disulfide (0.58 ml, 9.64 mmol) inpyridine (30 ml) was stirred at 60° C. for 3 hours. After cooling toroom temperature, the solid formed was filtered and dried to yield thedesired product (1.90 g, 84.9%). LCMS calculated for: C₁₁H₁₄N₆OS (M+H)280.1. found: 280.1.

Step B:3-(methylthio)-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

A solution of 9-pentyl-3-thioxo-2,3,6,9-tetrahydro-5h-[1,2,4]triazolo[4,3-a]purin-5-one (1.90 g, 6.83 mmol), dimethylsulfate (1.03 g, 8.19 mmol) and 1 m of sodium hydroxide in water (25 ml)was stirred at room temperature for 1 hour. The mixture was neutralizedto pH=7. The solid formed was filtered and dried to provide the desiredproduct (1.70 g, 85.2%). ¹HNMR (300 MHz, CD₃OD): δ 4.29 (t, J=7.2 Hz,2H), 2.65 (s, 3H), 1.89 (m, 2H), 1.40 (m, 4H), 0.92 (m, 3H). LCMScalculated for: C₁₂H₁₇N₆OS (M+H) 294.1. found: 294.1.

Step C:7-bromo-3-(methylthio)-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

A solution of 3-(methylthio)-9-pentyl-6,9-dihydro-5h-[1,2,4]triazolo[4,3-a]purin-5-one (111 mg, 0.380 mmol),N-bromosuccinimide (81.1 mg, 0.456 mmol) in THF (3 ml) was stirred at70° C. for 3 hours. The reaction was diluted with water and extractedwith ethyl acetate three times, dried with sodium sulfate, filtered, andconcentrated in vacuo. The crude residue was purified by Prep LCMS toyield the desired product. LCMS calculated for: C₁₂H₁₆BrN₆OS (M+H)371.0. found: 371.0, 373.0.

Example 107-bromo-3-(methylsulfinyl)-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

Step A:3-(methylsulfinyl)-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one(A1) and3-(methylsulfonyl)-9-pentyl-6,9-dihydro-5H-[7,2,4]triazolo[4,3-a]purin-5-one(A2)

To a solution of3-(methylthio)-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one(200 mg, 0.7 mmol) in THF (5 mL) was added m-chloroperbenzoic acid(283.3 mg, 1.64 mmol) at room temperature. After stirring at roomtemperature for 30 minutes, the reaction mixture was diluted with waterand extracted with ethyl acetate three times. The combined organiclayers were dried with sodium sulfate, filtered, and concentrated invacuo. The crude residue was purified by flash column chromatography toyield the desired products A1 and A2 as a mixture (A1:A2=3:2) (41 mg,8.5% for A1, 10% for A2). LCMS calculated for: C₁₂H₁₆N₆O₂S (A1) (M+H)309.1. found: 310.1. LCMS calculated for: C₁₂H₁₆N₆O₃S (A2) (M+H) 325.1.found: 325.1.

Step B:7-bromo-3-(methylsulfinyl)-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

To a mixture of 3-(methylsulfinyl)-9-pentyl-6,9-dihydro-5h-[1,2,4]triazolo[4,3-a]purin-5-one and3-(methylsulfonyl)-9-pentyl-6,9-dihydro-5h-[1,2,4]triazolo[4,3-a]purin-5-one (3:2, 125 mg, 0.40 mmol) in THF (3mL) was added N-bromosuccinimide (82.3 mg, 0.462 mmol) The mixture wasstirred at 70° C. for 3 hours. The reaction was diluted with water andextracted with ethyl acetate three times, dried with sodium sulfate,filtered, and concentrated in vacuo. The crude residue was purified byPrep LCMS to yield the desired product. LCMS calculated for:C₁₂H₁₅BrN₆O₂S (M+H) 387.0. found: 387.0, 389.0.

Example 117-bromo-3-(methylsulfonyl)-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 10. LCMS calculated for: C₁₂H₁₅BrN₆O₃S (M+H)403.0. found: 403.0, 405.0.

Example 127-bromo-3-hydroxy-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

Step A:3-hydroxy-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

A solution of (2z)-3-pentyl-3,7-dihydro-1 h-purine-2,6-dione 2-hydrazone(200 mg, 0.846 mmol), N,N-carbonyldiimidazole (1.65 g, 10.2 mmol) in THF(10 ml) was stirred at 70° C. overnight. The reaction mixture was thenheated in microwave reactor at 100° C. for 10 min. The reaction wascompleted checked by LCMS analysis. The reaction mixture wasconcentrated, diluted with EtOAc and washed with sat. NaHCO₃. Theaqueous was extracted with EtOAc (3×). The combined organic layers weredried (MgSO₄) and concentrated to yield the desired product (230 mg,98.4%). LCMS calculated for C₁₁H₁₅N₆O₂ (M+H) 263.1. found: 263.1.

Step B:7-bromo-3-hydroxy-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The mixture of solution of 3-hydroxy-9-pentyl-6,9-dihydro-5h-[1,2,4]triazolo[4,3-a]purin-5-one (100 mg, 0.381 mmol) andN-bromosuccinimide (204 mg, 1.14 mmol) in THF (2 ml) was stirred in amicrowave reactor at 70° C. for 10 min. The reaction mixture wasfiltrated and the filtrate was purified by prep LCMS to yield thedesired product. LCMS calculated for C₁₁H₁₄BrN₆O₂ (M+H) 341.0. found:341.0, 343.0.

Example 137-bromo-9-butyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

Step A: 9-butyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The mixture of (2E)-3-butyl-3,7-dihydro-1H-purine-2,6-dione 2-hydrazone(200 mg, 0.0009 mol) in Ethyl orthoformate (5 mL, 0.03 mol) was heatedat 100° C. overnight. After cooling to room temperature, the reactionmixture was filtrated and dried to give the desired product (150 mg,71.8%). LCMS calculated for C₁₀H₁₃N₆O (M+H): 233.1. found: 233.1.

Step B: 7-bromo-9-butyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

To a mixture of 9-butyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one(65 mg, 0.28 mmol) in THF (2 mL) was added N-bromosuccinimide (49.8 mg,0.280 mmol). The mixture was heated in a microwave reactor at 70° C. for10 minutes. The mixture was purified with prep LCMS to give the desiredproduct (4.8 mg, 6%). LCMS calculated for C₁₀H₁₂BrN₆O (M+H): 311.0.found: 311.0, 313.0.

Example 147-bromo-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 13. LCMS calculated for: C₁₁H₁₃BrN₆O (M+H) 325.0.found: 325.0, 327.0.

Example 157-bromo-9-pentyl-3-(methoxymethyl)-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

Step A:9-butyl-3-(methoxymethyl)-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The mixture of 9-butyl-3-(chloromethyl)-6,9-dihydro-5h-[1,2,4]triazolo[4,3-a]purin-5-one (35 mg, 125 mmol) in 4 M of sodiummethoxide in methanol (0.5 mL, 2 mmol) was stirred at room temperatureovernight. The reaction mixture was diluted with water and extractedwith ethyl acetate three times. The combined organic layers was driedwith sodium sulfate, filtered, and concentrated in vacuo to yield thedesired product (6 mg, 17.42%). LCMS calculated for C₁₃H₁₉N₆O₂ (M+H):290.2. found 290.2.

Step B:7-bromo-9-butyl-3-(methoxymethyl)-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The mixture of 9-butyl-3-(methoxymethyl)-6,9-dihydro-5h-[1,2,4]triazolo[4,3-a]purin-5-one (6 mg, 21.7 mmol),N-bromosuccinimide (4.64 mg, 26.0 mmol) in tetrahydrofuran (10 ml) wasstirred at 70° C. for 2 hours. The reaction mixture was concentrated invacuo and the residue was purified by prep LCMS to yield the desiredproduct. LCMS calculated for C₁₃H₁₈BrN₆O₂ (M+H): 369.1. found 371.1.

Example 167-bromo-9-pentyl-3-phenyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

Step A: benzaldehyde[(2E)-6-oxo-3-pentyl-1,3,6,7-tetrahydro-2H-purin-2-ylidene]hydrazone

A solution of (2E)-3-pentyl-3,7-dihydro-1 h-purine-2,6-dione 2-hydrazone(104 mg, 44 μmol), benzaldehyde (44.7 μl, 44 μmol) in ethanol (10 ml)was stirred at 70° C. for 3 hours. The reaction solution wasconcentrated in vacuo to give the desired product. LCMS calculated forC₁₇H₂₁N₆O (M+H): 325.2. found: 325.2.

Step B:9-pentyl-3-phenyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

A solution of benzaldehyde [(2E)-6-oxo-3-pentyl-1,3,6,7-tetrahydro-2h-purin-2-ylidene]hydrazone (140 mg, 0.432 mmol) in acetic acid (5 ml)was stirred at 130° C. for 5 hours. The reaction mixture wasconcentrated in vacuo and purified by prep LCMS to yield the desiredproduct (30 mg, 22% yield). LCMS calculated for C₁₇H₁₉N₆O (M+H): 323.2.found: 323.2.

Step C:7-bromo-9-pentyl-3-phenyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

To a mixture of 9-pentyl-3-phenyl-6,9-dihydro-5h-[1,2,4]triazolo[4,3-a]purin-5-one (30 mg, 0.093 mmol) in THF (30 mL)was added N-bromosuccinimide (19.9 mg, 0.112 mmol). The mixture wasstirred at 70° C. for 3 hours. The reaction mixture was concentrated invacuo and the crude residue was purified using preparative LCMS to yieldthe desired product (8.7 mg, 23.3% yield). LCMS calculated forC₁₇H₁₈BrN₆O (M+H) 401.1. found 401.1, 403.1

Example 177-bromo-9-pentyl-3-pyridin-3-yl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-onetrifluoroacetate

The title compound was prepared using procedures analogous to thosedescribed for Example 16. LCMS calculated for C₁₆H₁₇BrN₇O (M+H): 402.1.found: 402.1, 404.1.

Example 187-bromo-9-pentyl-3-pyridin-4-yl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-onetrifluoroacetate

The title compound was prepared using procedures analogous to thosedescribed for Example 16. LCMS calculated for C₁₆H₁₇BrN₇O (M+H): 402.1.found: 402.1, 404.1.

Example 197-bromo-9-pentyl-3-pyridin-2-yl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-onetrifluoroacetate

The title compound was prepared using procedures analogous to thosedescribed for Example 16. LCMS calculated for C₁₆H₁₇BrN₇O (M+H): 402.1.found: 402.1, 404.1.

Example 207-bromo-9-pentyl-3-(1,3-thiazol-2-yl)-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 16. LCMS calculated for C₁₄H₁₅BrN₇OS (M+H): 408.0.found: 408.1.

Example 217-bromo-9-pentyl-3-propyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 5. LCMS calculated for C₁₄H₂₀BrN₆O: 367.1. found;367.1, 369.1.

Example 227-bromo-3-[(dimethylamino)methyl]-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-onetrifluoroacetate

The mixture of7-bromo-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one (130mg, 0.40 mmol) and Eschenmoser's salt (1.1 eq.) in DMF (5 mL) was heatedat 100° C. for 30 minutes. The reaction mixture was directly purifiedusing preparative LCMS to yield the desired product. LCMS calculated forC₁₄H₂₁BrN₇O: 382.1. found 382.1, 384.1.

Example 233-methyl-9-pentyl-7-(1,3-thiazol-2-yl)-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

Step A:7-bromo-6-(4-methoxybenzyl)-3-methyl-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The mixture of 7-bromo-3-methyl-9-pentyl-6,9-dihydro-5h-[1,2,4]triazolo[4,3-a]purin-5-one (200 mg, 0.59 mmol), 4-methoxyphenylmethylbromide (0.094 mL, 0.65 mmol), potassium carbonate (244 mg, 1.77mmol) in DMF (10 ml) was stirred at room temperature for 2 hours. Thereaction was quenched with water and the solid formed was filtered anddried over to yield the desired product (270 mg, 99.7%). LCMS calculatedfor C₂₀H₂₄BrN₆O₂: 459.1. found 460.1.

Step B:6-(4-methoxybenzyl)-3-methyl-9-pentyl-7-(1,3-thiazol-2-yl)-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

To the mixture of7-bromo-6-(4-methoxybenzyl)-3-methyl-9-pentyl-6,9-dihydro-5h-[1,2,4]triazolo[4,3-a]purin-5-one (100 mg, 0.22 mmol),2-(tributylstannyl)-1,3-thiazole (122 mg, 0.33 mmol) in toluene (14 mL)was added tetrakis(triphenylphosphine)palladium(0) (12.6 mg, 0.011 mmol)under N₂. The mixture was refluxed overnight. The reaction mixture wasconcentrated in vacuo. The crude residue was purified using preparativeLCMS to yield the desired product (80 mg, 79%). LCMS calculated forC₂₃H₂₆N₇O₂S (M+H): 464.2. found 464.2.

Step C:3-methyl-9-pentyl-7-(1,3-thiazol-2-yl)-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The mixture of6-(4-methoxybenzyl)-3-methyl-9-pentyl-7-(1,3-thiazol-2-yl)-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one(100 mg, 0.22 mmol) in trifluoroacetic acid (5 mL, 65 mmol) was stirredat 55° C. overnight. The reaction solution was concentrated and purifiedusing preparative LCMS to yield the desired product. LCMS calculated forC₁₅H₁₈N₇OS: 344.1. found: 344.1.

Example 243-methyl-7-(methylthio)-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

Step A:6-(4-methoxybenzyl)-3-methyl-7-(methylthio)-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

A mixture of 7-bromo-6-(4-methoxybenzyl)-3-methyl-9-pentyl-6,9-dihydro-5h-[1,2,4]triazolo[4,3-a]purin-5-one (271 mg, 0.6 mmol) and sodium methylsulfide (45.5 mg, 0.65 mmol) in dimethoxyethane (13.4 ml, 129 mmol) wasrefluxed for 2 h. The reaction was quenched with water. The solid formedwas filtered and dried to yield the desired product (200 mg, 79.5%).LCMS calculated for C₂₁H₂₇N₆O₂S (M+H): 427.2. found 427.2.

Step B:3-methyl-7-(methylthio)-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

A solution of6-(4-methoxybenzyl)-3-methyl-7-(methylthio)-9-pentyl-6,9-dihydro-5h-[1,2,4]triazolo[4,3-a]purin-5-one (200 mg, 469 mmol) intrifluoroacetic acid (5 ml, 64.9 mmol) was stirred at 55° C. overnight.The solution was concentrated and purified by prep LCMS to yield thedesired product (60 mg, 42%). ¹HNMR (300 MHz, CD₃OD): δ 4.42 (t, J=7.5Hz, 2H), 2.74 (s, 3H), 2.45 (s, 3H), 1.92 (m, 2H), 1.39 (m, 4H), 0.92(m, 3H). LCMS calculated for C₁₃H₁₉N₆OS (M+H): 307.1. found 307.1.

Example 253-methyl-9-pentyl-7-phenyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

To a mixture of 7-bromo-3-methyl-9-pentyl-6,9-dihydro-5h-[1,2,4]triazolo[4,3-a]purin-5-one (100 mg, 0.30 mmol), phenylboronicacid (39.5 mg, 0.32 mmol), sodium carbonate (100 mg, 0.94 mmol) in water(2 ml) and 1,2-dimethoxyethane (20 ml) was addedtetrakis(triphenylphosphine)-palladium(0) (200 mg, 0.10 mmol) Themixture was heated to reflux overnight. The reaction mixture was dilutedwith water and extracted with ethyl acetate three times. The combinedorganic layers were dried with sodium sulfate, filtered, andconcentrated in vacuo. The residue was purified by preparative LCMS toyield the desired product (16 mg, 16%). ¹HNMR (400 MHz, CD₃OD): δ 8.06(m, 2H), 7.49 (m, 3H), 4.38 (t, J=8.0 Hz, 2H), 2.83 (s, 3H), 1.95 (m,2H), 1.42 (m, 4H), 0.92 (m, 3H). LCMS calculated for C₁₈H₂₁N₆O (M+H):337.2. found 337.2.

Example 263-methyl-9-pentyl-7-pyridin-4-yl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-onetrifluoroacetate

To a mixture of 7-bromo-3-methyl-9-pentyl-6,9-dihydro-5h-[1,2,4]triazolo[4,3-a]purin-5-one (100 mg, 0.30 mmol),4-pyridinylboronic acid (40 mg, 0.32 mmol), sodium carbonate (100 mg,0.94 mmol) in water (2 ml) and toluene (20 ml) was addedtetrakis(triphenylphosphine)palladium(0) (200 mg, 0.10 mmol) The mixturewas heated to reflux overnight. The reaction mixture was diluted withwater and extracted with ethyl acetate three times. The combined organiclayers were dried with sodium sulfate, filtered, and concentrated invacuo. The residue was purified by preparative LCMS to yield the desiredproduct (16 mg, 16%). ¹HNMR (400 MHz, CD₃OD): δ 8.83 (dd, J=1.6, 4.9 Hz,2H), 8.33 (dd, J=1.6, 4.9 Hz, 2H), 4.44 (t, J=7.7 Hz, 2H), 2.88 (s, 3H),1.97 (m, 2H), 1.44 (m, 4H), 0.93 (m, 3H). LCMS calculated for C₁₇H₂₀N₇O(M+H): 338.2. found 338.2.

Example 277-(3,5-dimethylisoxazol-4-yl)-3-methyl-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 25. LCMS calculated for C₁₇H₂₂N₇O₂ (M+H): 356.2.found 356.2.

Example 287-cyclopropyl-3-methyl-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 25. ¹HNMR (300 MHz, d₆-DMSO): δ 4.18 (d, J=7.5 Hz,2H), 2.70 (s, 3H), 2.05 (m, 1H), 1.78 (m, 2H), 1.28 (m, 4H), 1.06 (m,4H), 0.92 (m, 3H). LCMS calculated for C₁₅H₂₁N₆O (M+H): 301.2. found301.2.

Example 293-methyl-7-(1-methyl-1H-pyrazol-4-yl)-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

Step A:6-(4-methoxybenzyl)-3-methyl-7-(1-methyl-1H-pyrazol-4-yl)-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

To a solution of7-bromo-6-(4-methoxybenzyl)-3-methyl-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one(100 mg, 0.3 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (92mg, 0.44 mmol) and sat. sodium carbonate (100 mg, 0.9 mmol) in toluene(20 mL, 0.2 mol) was added tetrakis(triphenylphosphine)palladium(0) (20mg, 0.01 mmol) under N₂ at room temperature. The mixture was heated toreflux overnight. The mixture was stripped down and purified bypreparative LC-MS to yield the desired product (50 mg, 37%). LCMScalculated for C₂₄H₂₉N₈O₂ (M+H): 461.2. found 461.2.

Step B:3-methyl-7-(1-methyl-M-pyrazol-4-yl)-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

6-(4-Methoxybenzyl)-3-methyl-7-(1-methyl-1H-pyrazol-4-yl)-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one(50 mg, 0.10 mmol) in trifluoroacetic acid (5 mL) was stirred at 60° C.overnight. The mixture was concentrated, and the residue was purified bypreparative LC-MS to give final product. ¹HNMR (300 MHz, CD₃OD): δ 8.23(d, J=4.9 Hz, 1H), 8.05 (d, J=4.9 Hz, 1H), 4.45 (t, J=7.0 Hz, 2H), 3.98(s, 3H), 2.46 (s, 3H), 1.93 (m, 2H), 1.41 (m, 4H), 0.92 (m, 3H). LCMScalculated for C₁₆H₂₁N₈O (M+H): 341.2. found 341.2.

Example 303-methyl-9-pentyl-7-(4H-1,2,4-triazol-4-yl)-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

Step A:6-(4-methoxybenzyl)-3-methyl-9-pentyl-7-(4H-1,2,4-triazol-1-yl)-6,9-dihydro-5H-[1,2,4]triazolo[4,3-c]purin-5-one

Sodium hydride 60% in mineral oil (18 mg, 0.74 mmol) was added to asolution of 1H-1,2,4-Triazole (45 mg, 0.65 mmol) in DMF (10 mL) at roomtemperature. After stirring for 1 hour at room temperature,7-bromo-6-(4-methoxybenzyl)-3-methyl-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one(200 mg, 0.40 mmol) in DMF was added to above solution and the mixturewas stirred overnight. The reaction was quenched with a drop of waterand the reaction mixture was purified by pre LC-MS to give the desiredproduct (53 mg, 27.2%) and its region-isomer6-(4-methoxybenzyl)-3-methyl-9-pentyl-7-(1H-1,2,4-triazol-1-yl)-6,9-dihydro-5H-[1,2,4]triazolopurin-5-one (53 mg, 27%). LCMS calculated for C₂₂H₂₆N₉O₂ (M+H): 448.2.found 448.2.

Step B:3-methyl-9-pentyl-7-(4H-1,2,4-triazol-4-yl)-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

A mixture of6-(4-methoxybenzyl)-3-methyl-9-pentyl-7-(1H-1,2,4-triazol-1-yl)-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one(53 mg, 0.12 mmol) in trifluoroacetic acid (10 mL) was stirred at 60° C.overnight. The mixture was concentrated and purified by preparativeLC-MS to give the desired product (20 mg, 52%). LCMS calculated forC₁₄H₁₈N₉O (M+H): 328.2. found: 328.2.

Example 313-methyl-9-pentyl-7-(1H-1,2,4-triazol-1-yl)-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 30. LCMS calculated for C₁₄H₁₈N₉O (M+H): 328.2.found: 328.2.

Example 327-cyclobutyl-3-methyl-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

Step A:N-(5-amino-6-oxo-3-pentyl-2-thioxo-1,2,3,6-tetrahydropyrimidin-4-yl)cyclobutanecarboxamide

The mixture of5,6-diamino-1-pentyl-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (1060 mg,0.00464 mol), cyclobutane carboxylic acid (0.55 g, 5.5 mmol),benzotriazol-1-yloxytris-(dimethylamino)phosphonium hexafluorophosphate(2.2 g, 5.1 mmol) and triethylamine (1.3 mL, 9.3 mmol) in DMF (20 mL)was stirred at room temperature for 4 hours. The mixture was dilutedwith water. The precipitate formed was filtered and dried to yield thedesired product (1.20 g, 83.27%). LCMS calculated for C₁₄H₂₃N₄O₂S (M+H):311.2. found 311.2.

Step B: 8-cyclobutyl-3-pentyl-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one

The mixture ofN-(5-amino-6-oxo-3-pentyl-2-thioxo-1,2,3,6-tetrahydropyrimidin-4-yl)cyclobutanecarboxamide(720 mg, 2.3 mmol) and 2.5 M of sodium hydroxide in water (25 mL) andmethanol (25 mL) was stirred at 70° C. for 1 hour. After cooling to roomtemperature, The reaction mixture was concentrated to remove methanoland then acidified to pH=5. The precipitate formed was filtered anddried to yield the desired product (500 mg, 73.7%). LCMS calculated forC₁₄H₂₁N₄OS (M+H): 293.1. found: 293.1.

Step C: (2E)-8-cyclobutyl-3-pentyl-3,7-dihydro-1H-purine-2,6-dione2-hydrazone

The mixture of8-cyclobutyl-3-pentyl-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one (0.6 g,2.0 mmol) in 20 M of hydrazine in water (20 mL) was stirred at 100° C.overnight. After cooling to room temperature, the solid formed wasfiltered and dried Cooled down, the solid was isolated to give yield thedesired product (230 mg, 38.6%). LCMS calculated for C₁₄H₂₃N₆O (M+H):291.2. found: 291.2.

Step D:7-cyclobutyl-3-methyl-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

(2E)-8-cyclobutyl-3-pentyl-3,7-dihydro-1H-purine-2,6-dione 2-hydrazone(100 mg, 0.0003 mol) was mixed with triethyl orthoacetate (10 mL, 0.05mol) and then stirred at 100° C. overnight. After cooling to roomtemperature, the mixture was concentrated and purified by preparativeLCMS to yield the desired product (10 mg, 9.2%). ¹HNMR (300 MHz, CD₃OD):δ 4.35 (m, 2H), 3.72 (m, 1H), 2.84 (s, 3H), 2.44 (m, 4H), 2.05 (m, 2H),1.90 (m, 2H), 1.40 (m, 4H), 0.92 (m, 3H). LCMS calculated for C₁₆H₂₃N₆O(M+H): 315.2. found: 315.2.

Example 337-bromo-3-(4-methoxyphenyl)-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 16. ¹HNMR (300 MHz, CD₃OD): δ 7.67 (d, J=9.2 Hz,2H), 7.03 (d, J=9.2 Hz, 2H), 4.41 (t, J=7.8 Hz, 2H), 3.88 (s, 3H), 1.96(m, 2H), 1.44 (m, 4H), 0.94 (m, 3H). LCMS calculated for C₁₈H₂₀BrN₆O₂(M+H): 431.1. found 431.1.

Example 347-bromo-9-pentyl-3-(4-(trifluoromethyl)phenyl)-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 16. ¹HNMR (300 MHz, CD₃OD): δ 7.94 (d, J=8.6 Hz,2H), 7.78 (d, J=9.2 Hz, 2H), 4.44 (t, J=7.3 Hz, 2H), 1.97 (m, 2H), 1.44(m, 4H), 0.94 (m, 3H). LCMS calculated for C₁₈H₁₆BrF₃N₆O (M+H): 469.1.found 469.1.

Example 357-bromo-3-(4-methoxybenzyl)-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

Step A:2-(4-methoxyphenyl)-N′-[(2E)-6-oxo-3-pentyl-1,3,6,7-tetrahydro-2H-purin-2-ylidene]acetohydrazide

The mixture of (2E)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione 2-hydrazone(0.30 g, 1.3 mmol), benzeneacetic acid, 4-methoxy-(0.23 g, 1.4 mmol),benzotriazol-1-yloxytris-(dimethylamino)phosphonium hexafluorophosphate(0.62 g, 1.40 mol) and triethylamine (0.53 mL, 3.8 mmol) in DMF (10 mL)were stirred at room temperature overnight. The reaction mixture wasdiluted with ethyl acetate and washed sat. NaHCO₃. The aqueous wasextracted with ethyl acetate (3 x). The combined organic layers weredried (MgSO₄), filtered and concentrated to yield the desired product(560 mg, 98%). LCMS calculated for C₁₉H₂₅N₆O₃ (M+H): 385.2. found:385.2.

Step B:3-(4-methoxybenzyl)-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The mixture of2-(4-methoxyphenyl)-N′-[(2E)-6-oxo-3-pentyl-1,3,6,7-tetrahydro-2H-purin-2-ylidene]acetohydrazide(0.66 g, 1.4 mmol) in toluene (30 mL) was refluxed overnight. Thereaction mixture was concentrated to give the crude product as a solid.The solid was washed with ethyl acetate and dried to yield the desiredproduct (490 mg, 92%). LCMS calculated for C₁₉H₂₃N₆O₂ (M+H): 367.2.found: 367.2.

Step C:7-bromo-3-(4-methoxybenzyl)-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

To the solution of3-(4-methoxybenzyl)-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one(0.40 g, 1.1 mmol) in THF was added N-Bromosuccinimide (0.29 g, 1.6mol). The mixture was stirred at 70° C. for 1 hour. The mixture wasconcentrated and purified by preparative LCMS to yield the desiredproduct (290 mg, 60%). ¹HNMR (300 MHz, d₆-DMSO): δ 7.16 (d, J=8.3 Hz,2H), 6.81 (d, J=8.3 Hz, 2H), 4.46 (s, 3H), 4.20 (t, J=7.2 Hz, 2H), 3.67(s, 2H), 1.79 (m, 2H), 1.28 (m, 4H), 0.83 (m, 3H). LCMS calculated forC₁₉H₂₁BrN₆O₂ (M+H): 445.1. found: 445.0, 447.0.

Example 367-bromo-9-pentyl-3-(3-bromobenzyl)-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

Step A:2-(3-bromophenyl)-N′-[(2E)-6-oxo-3-pentyl-1,3,6,7-tetrahydro-2H-purin-2-ylidene]acetohydrazide

The mixture of (2E)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione 2-hydrazone(0.30 g, 1.3 mmol), (3-bromophenyl)acetic acid (0.30 g, 1.4 mol),benzotriazol-1-yloxytris-(dimethylamino)phosphonium hexafluorophosphate(0.62 g, 1.4 mol) and triethylamine (0.53 mL, 3.8 mmol) in DMF (10 mL)were stirred at rt overnight. The reaction mixture was diluted withEtOAc. The solid was filtered, washed with EA and dried to yield thedesired product (430 mg, 78.2%). LCMS calculated for C₁₈H₂₂BrN₆O₂ (M+H):433.1. found: 433.1.

Step B:3-(3-bromobenzyl)-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The mixture of2-(3-bromophenyl)-N′-[(2E)-6-oxo-3-pentyl-1,3,6,7-tetrahydro-2H-purin-2-ylidene]acetohydrazide(1.8 g, 4.2 mmol) in benzene (100 mL) was refluxed overnight. Thereaction mixture was concentrated to give the desired product 1.5 g.LCMS calculated for C₁₈H₂₀BrN₆O (M+H): 415.1. found: 415.1.

Step C:7-bromo-9-pentyl-3-(3-bromobenzyl)-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

To the solution of3-(3-bromobenzyl)-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one(210 mg, 0.50 mmol) in tetrahydrofuran (20 mL) was addedN-bromosuccinimide (140 mg, 0.00076 mol). The mixture was stirred at 70°C. for 1 hour. The reaction mixture was concentrated and the residue waspurified by preparative LCMS to yield the desired product (0.15 g, 60%).¹HNMR (300 MHz, d₆-DMSO): δ 7.16 (d, J=8.3 Hz, 2H), 6.81 (d, J=8.3 Hz,2H), 4.46 (s, 3H), 4.20 (t, J=7.2 Hz, 2H), 3.67 (s, 2H), 1.79 (m, 2H),1.28 (m, 4H), 0.83 (m, 3H). LCMS calculated for C₁₈H₁₉Br₂N₆O (M+H): 493.found: 493, 495 and 497.

Example 377-bromo-9-pentyl-3-(3-pyrimidin-5-ylbenzyl)-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-onetrifluoroacetate

The title compound was prepared using procedures analogous to thosedescribed for Example 35. LCMS calculated for C₂₃H₂₁BrN₈O (M+H): 493.1.found: 493.1, 495.1.

Example 387-bromo-9-pentyl-3-pyrimidin-4-yl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 35. ¹HNMR (400 MHz, CD₃OD): δ 9.30 (d, J=1.3 Hz,1H), 8.96 (d, J=5.2 Hz, 1H), 7.96 (d, J=5.3, 1.3 Hz, 1H), 4.47 (t, J=7.4Hz, 2H), 1.99 (m, 2H), 1.46 (m, 4H), 0.96 (m, 3H). LCMS calculated forC₁₅H₁₅BrN₈O (M+H): 403.1. found: 403.1, 405.1.

Example 397-bromo-9-pentyl-3-pyrazin-2-yl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-onetrifluoroacetate

The title compound was prepared using procedures analogous to thosedescribed for Example 35. ¹HNMR (400 MHz, CD3OD): δ 9.30-9.25 (d, J=1.0Hz, 1H), 8.95-8.90 (dd, J=1.0, 3.0 Hz, 1H), 7.95-7.91 (dd, J=1.0, 3.0Hz, 1H), 4.50-4.40 (m, 2H), 2.00-1.90 (m, 2H), 1.48-1.40 (m, 4H),0.95-0.90 (m, 3H). LCMS calculated for C₁₅H₁₅BrN₈O (M+H): 403.1. found:403.1, 405.1.

Example 407-bromo-3-cyclopropyl-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 16. ¹HNMR (300 MHz, d₆-DMSO): δ 4.18 (t, J=7.6 Hz,3H), 2.82 (m, 1H), 1.77 (m, 2H), 1.28 (m, 4H), 0.99 (m, 4H), 0.83 (m,3H). LCMS calculated for C₁₄H₁₇BrN₆O (M+H): 365.1. found: 365.1, 365.1.

Example 417-bromo-3-(dimethylamino)-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-onetrifluoracetate

Step A:3-(dimethylamino)-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

To methylene chloride (10 mL) was added [B]N-(dichloromethylene)-N-methylmethanaminium chloride (0.21 g, 1.3 mmol)After stirring for 5 mins, (2Z)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione2-hydrazone (0.10 g, 0.42 mmol) was added, and the mixture was stirredat rt for 5 hrs. LCMS analysis showed product as a major peak wasformed. 1N NaOH was carefully added to neutralize the acid, and themixture was extracted with methylene chloride three times. The combinedorganic layers were dried by MgSO₄, filtered and concentrated in vacuoto yield the desired product (84 mg, 69%). LCMS calculated for C₁₃H₂₀N₇O(M+H): 290.2. found 290.1.

Step B:7-bromo-3-(dimethylamino)-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-onetrifluoroacetate

To a mixture of3-(dimethylamino)-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one(80 mg, 0.28 mmol) in Tetrahydrofuran (20 mL) was addedN-Bromosuccinimide (59 mg, 0.33 mol). The mixture was stirred at 70° C.for 1 hour. The reaction mixture was concentrated and purified bypreparative LCMS to provide the desired product. LCMS calculated forC₁₃H₁₉BrN₇O (M+H): 368.1. found: 368.0, 370.0.

Example 427-bromo-9-pentyl-3-(3,3,3-trifluoropropyl)-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 16. LCMS calculated for C₁₄H₁₆BrF₃N₆O (M+H):421.1. found: 421.1, 423.1.

Example 437-bromo-9-pentyl-3-(2-phenylethyl)-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 16. ¹HNMR (300 MHz, CD₃OD): δ 7.23 (m, 5H), 4.32(t, J=8.0 Hz, 2H), 3.53 (t, J=8.0 Hz, 2H), 3.11 (t, J=8.0 Hz, 2H), 1.90(m, 2H), 1.40 (m, 4H), 0.92 (m, 3H). LCMS calculated for C₁₉H₂₁BrN₆O(M+H): 429.1. found: 429.1, 431.1.

Example 447-bromo-9-pentyl-3-(trifluoromethyl)-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

Step A:9-pentyl-3-(trifluoromethyl)-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The mixture of (2E)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione 2-hydrazone(200 mg, 0.85 mol) in trifluoroacetic acid (10 mL) was refluxedovernight. The reaction mixture was concentrated and purified bypreparative LCMS to yield the desired product (160 mg, 60.2%). LCMScalculated for C₁₂H₁₄F₃N₆O (M+H): 315.1. found 315.0.

Step B:7-bromo-9-pentyl-3-(trifluoromethyl)-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

To the mixture of9-pentyl-3-(trifluoromethyl)-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one(50 mg, 0.16 mmol) in tetrahydrofuran (10 mL) was addedN-bromosuccinimide (42 mg, 0.24 mmol). The mixture was stirred at 70° C.for 3 hour. The reaction mixture was concentrated and purified bypreparative LCMS to yield the desired product. ¹HNMR (300 MHz, CD₃OD): δ4.44 (t, J=7.6 Hz, 2H), 1.94 (m, 2H), 1.42 (m, 4H), 0.93 (m, 3H). LCMScalculated for C₁₂H₁₃BrF₃N₆O (M+H): 393.0. found: 393.0, 395.0.

Example 457-bromo-9-pentyl-3-(pyridine-4-ylmethyl)-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-onetrifluoroacetate

The title compound was prepared using procedures analogous to thosedescribed for Example 35. LCMS calculated for C₁₇H₁₈BrN₇O (M+H): 416.1.found: 416, 418.

Example 467-bromo-9-pentyl-3-(2-pyridine-3-ylethyl)-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-onetrifluoroacetate

The title compound was prepared using procedures analogous to thosedescribed for Example 35. LCMS calculated for C₁₈H₂₀BrN₇O (M+H): 429.1.found: 430.0, 432.0.

Example 477-bromo-9-pentyl-3-(1-phenylcyclopropyl)-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 35. LCMS calculated for C₂₀H₂₁BrN₆O (M+H): 441.1.found: 441.0, 443.0.

Example 487-bromo-3-(2-methylpyridin-4-yl)-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-onetrifluoroacetate

The title compound was prepared using procedures analogous to thosedescribed for Example 16. LCMS calculated for C₁₇H₁₈BrN₇O (M+H): 416.1.found: 416.0, 418.0.

Example 497-bromo-3-(3-fluoropyridin-4-yl)-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-onetrifluoroacetate

The title compound was prepared using procedures analogous to thosedescribed for Example 16. LCMS calculated for C₁₆H₁₅BrFN₇O (M+H): 421.1.found: 421.0, 423.0.

Example 507-bromo-3-(3-fluorobenzyl)-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 35. LCMS calculated for C₁₈H₁₈BrFN₆O (M+H): 433.1.found: 433.0, 435.0.

Example 517-bromo-3-(3-methoxybenzyl)-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 35. LCMS calculated for C₁₉H₂₁BrN₆O₂ (M+H): 445.1.found: 445.1, 447.0.

Example 527-bromo-3-(1,3-oxazol-4-yl)-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 35. ¹HNMR (300 MHz, CD₃OD): δ 8.68 (d, J=0.9 Hz,1H), 8.33 (d, J=0.9 Hz, 1H), 4.40 (t, J=7.3 Hz, 2H), 1.95 (m, 2H), 1.42(m, 4H), 0.93 (m, 3H). LCMS calculated for C₁₄H₁₄BrN₇O₂ (M+H): 392.1.found: 392.0, 394.0.

Example 537-bromo-3-isoxazol-3-yl-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 35. ¹HNMR (300 MHz, CD₃OD): δ 8.85 (d, J=1.8 Hz,1H), 6.97 (d, J=1.8 Hz, 1H), 4.45 (t, J=7.5 Hz, 2H), 1.96 (m, 2H), 1.43(m, 4H), 0.94 (m, 3H). LCMS calculated for C₁₄H₁₄BrN₇O₂ (M+H): 392.1.found: 392,0, 394.0.

Example 547-bromo-3-(1-methyl-1H-imidazol-2-yl)-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one trifluoroacetate

The title compound was prepared using procedures analogous to thosedescribed for Example 35. LCMS calculated for C₁₅H₁₇BrN₈O (M+H): 405.1.found: 405.0, 407.0.

Example 557-bromo-9-pentyl-3-(3-pyridin-4-ylbenzyl)-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-onetrifluoroacetate

The title compound was prepared using procedures analogous to thosedescribed for Example 35. LCMS calculated for C₂₃H₂₂BrN₇O (M+H): 492.1.found: 492.1, 494.1.

Example 567-bromo-3-(2-methoxybenzyl)-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 35. LCMS calculated for C₁₉H₂₁BrN₆O₂ (M+H): 445.1.found: 445,0, 447.0.

Example 571-(7-bromo-5-oxo-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-3-yl)cyclopropanecarboxamide

The title compound was prepared using procedures analogous to thosedescribed for Example 35. ¹HNMR (300 MHz, CD₃OD): δ 4.35 (t, J=7.0 Hz,2H), 1.92 (m, 2H), 1.68 (m, 2H), 1.51 (m, 2H), 1.43 (m, 4H), 0.94 (m,3H). LCMS calculated for C₁₅H₁₈BrN₇O₂ (M+H): 408.1. found: 408.0, 410.0.

Example 581-(7-bromo-5-oxo-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-3-yl)cyclopropanecarboxylicacid

The title compound was prepared using procedures analogous to thosedescribed for Example 35. ¹HNMR (300 MHz, CD₃OD): δ 4.35 (t, J=7.3 Hz,2H), 1.91 (m, 2H), 1.72 (m, 2H), 1.62 (m, 2H), 1.41 (m, 4H), 0.92 (m,3H). LCMS calculated for C₁₅H₁₇BrN₆O₃ (M+H): 409.1. found: 409,0, 411.0.

Example 597-bromo-9-pentyl-3-[1-(trifluoromethyl)cyclopropyl]-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 35. ¹HNMR (300 MHz, CD₃OD): δ 4.37 (t, J=7.7 Hz,2H), 1.91 (m, 2H), 1.62 (m, 2H), 1.54 (m, 2H), 1.41 (m, 4H), 0.92 (m,3H). LCMS calculated for C₁₅H₁₆BrF3N₆O (M+H): 433.1. found: 433,0,435.0.

Example 607-bromo-3-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 35. ¹HNMR (300 MHz, d₆-DMSO): δ 6.71 (m, 3H), 4.41(s, 2H), 4.20 (t, J=7.7 Hz, 2H), 4.15 (s, 4H), 1.79 (m, 2H), 1.29 (m,4H), 0.84 (m, 3H). LCMS calculated for C₂₀H₂₁BrN₆O₃ (M+H): 473.1. found:473,0, 475.0.

Example 617-bromo-3-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)methyl])-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 35. LCMS calculated for C₂₀H₂₀BrN₇O₃ (M+H): 486.1.found: 486,0, 488.0.

Example 623-Benzyl-7-bromo-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 16. LCMS calculated for C₁₈H₁₉BrN₆O (M+H): 415.1.found: 415,0, 417.0.

Example 637-bromo-3-ethyl-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 5. ¹HNMR (400 MHz, d₆-DMSO): δ 4.18 (t, J=7.0 Hz,2H), 3.33 ((br, 1H), 3.14 (dd, J=7.5 Hz, 2H), 1.78 (m, 2H), 1.27 (m,7H), 0.83 (m, 3H). LCMS calculated for C₁₈H₁₉BrN₆O (M+H): 353.1. found:353,0, 353.0.

Example 64 6-bromo-4-pentyl-4,7-dihydro-8H-tetrazolo[1,5-a]purin-8-one

Step A: 4-pentyl-4,7-dihydro-8H-tetrazolo[1,5-c]purin-8-one

A saturated aqueous NaNO₂ (130 mg, 1.89 mmol) solution was addeddropwise to a solution of (2E)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione2-hydrazone (150 mg, 0.63 mmol) in 5% aqueous HCl solution (3 ml) understirring at room temperature. The mixture was stirred at roomtemperature for 1 hour. The mixture was neutralized by saturated NaHCO₃solution and extracted by ethyl acetate (3×). The combined organicphases were washed by brine and dried over MgSO₄. The filtration andevaporation of solvent gave the desired product (94.6 mg, 60.7%) aswhite solid. LCMS calculated for C₁₀H₁₄N₇O (M+H): 248.1. found: 248.0.

Step B: 6-bromo-4-pentyl-4,7-dihydro-8H-tetrazolo[1,5-c]purin-8-one

The mixture of 4-pentyl-4,7-dihydro-8H-tetrazolo[1,5-a]purin-8-one (94.6mg, 0.38 mmol) and NBS (75 mg, 0.42 mmol) in THF (20 ml) was stirred at70° C. for 1 hour. After evaporation of solvent, the residue waspurified by preparative LC-MS to yield the desired product (17.1 mg,13.7%). LCMS calculated for C₁₀H₁₃BrN₇O (M+H): 326.0. found: 326.0.

Example 653-(7-bromo-5-oxo-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-3-yl)propanoicacid

Step A:(4E)-4-[(2E)-(6-oxo-3-pentyl-1,3,6,7-tetrahydro-2H-purin-2-ylidene)hydrazono]butanoicacid

The mixture of (2E)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione 2-hydrazone(1.0 g, 4.2 mmol) and 4-oxobutanoic acid (3.4 g, 15% in water, 5.1 mmol)in EtOH (70 ml) was refluxed for 1.5 hours. Evaporation of solvent gavethe desired product (1.3 g, 96%) as a yellowish solid. LCMS calculatedfor C₁₄H₂₁N₆O₃ (M+H): 321.1. found: 321.1.

Step B:3-(5-oxo-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-3-yl)propanoicacid

The mixture of(4E)-4-[(2E)-(6-oxo-3-pentyl-1,3,6,7-tetrahydro-2H-purin-2-ylidene)hydrazono]butanoicacid (1.367 g, 5.1 mmol) in acetic acid (70 ml) was refluxed for 1 hour.Evaporation of solvent afforded the desired product (1.29 g, 99%) asyellowish solid. LCMS calculated for C₁₄H₁₉N₆O₃ (M+H): 319.2. found:319.2.

Step C:3-(7-bromo-5-oxo-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-3-yl)propanoicacid

The mixture of3-(5-oxo-9-pentyl-6,9-dihro-5H[1,2,4]triazolo[4,3-a]purin-3-yl)propanoicacid (203 mg, 0.64 mmole) and NBS (125.8 mg, 7.0 mmol) in THF (25 ml)was stirred at 70° C. for 2 hours. After evaporation of solvent, theresidue was purified by preparative LC-MS to afford 60.2 mg (23.7%) ofthe desired product (60.2 mg, 23.7%) as white solid. LCMS calculated forC₁₄H₁₈BrN₆O₃ (M+H): 397.1. found: 371.1.

Example 667-bromo-3-(3-morpholin-4-yl-3-oxopropyl)-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The mixture of3-(7-bromo-5-oxo-9-pentyl-6,9-dihydro-5H[1,2,4]triazolo[4,3-a]purin-3-yl]propanoicacid (50 mg, 0.126 mmol), morpholine (21.0 mg, 0.252 mmol),triethylamine (25.5 mg, 0.252 mmol) and BOP (61.5 mg, 0.139 mmol) inCH₂Cl₂ (10 ml) was stirred at room temperature for 2 hours. Afterevaporation of solvent, the residue was purified by preparative LC-MS toafford the desired product (37.2 mg, 60%) as white solid. LCMScalculated for C₁₈H₂₅BrN₇O₃ (M+H): 466.1. found: 466.1.

Example 67N-benzyl-3-(7-bromo-5-oxo-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-3-yl)propanamide

The title compound was prepared using procedures analogous to thosedescribed for Example 66. ¹HNMR (400 MHz, d₆-DMSO): δ 8.43 (m, 1H), 7.25(m, 5H), 4.22 (m, 4H), 3.42 (m, 2H), 2.68 (m, 2H), 1.79 (m, 2H), 1.30(m, 4H), 0.84 (m, 3H). LCMS calculated for C₂₁H₂₅BrN₇O₂ (M+H): 486.1.found: 486.1, 488.0.

Example 687-bromo-3-(3-oxo-3-pyrrolidin-1-ylpropyl)-9-pentyl-6,9-dihydro-5H-pyrrolo[3,2-d][1,2,4]triazolo[4,3-a]pyrimidin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 66. ¹HNMR (400 MHz, d₆-DMSO): δ 4.19 (t, J=7.2 Hz,2H), 3.40 ((m, 4H), 3.26 (t, J=6.8 Hz, 2H), 2.73 (t, J=7.2 Hz, 2H), 1.80(m, 6H), 1.29 (m, 4H), 0.83 (m, 3H). LCMS calculated for C₁₉H₂₆BrN₆O₂(M+H): 449.130. found 449.1, 451.1.

Example 693-(7-bromo-5-oxo-9-pentyl-6,9-dihydro-5H-pyrrolo[3,2-d][1,2,4]triazolo[4,3-a]pyrimidin-3-yl)-N-methylpropanamide

The title compound was prepared using procedures analogous to thosedescribed for Example 66. LCMS calculated for C₁₆H₂₂BrN₆O₂ (M+H): 409.1.found: 409.1, 411.1.

Example 703-(7-bromo-5-oxo-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-3-yl)-N-(2-phenylethyl)propanamide

The title compound was prepared using procedures analogous to thosedescribed for Example 66. ¹HNMR (400 MHz, d₆-DMSO): δ 8.01 (t, J=5.3 Hz,1H), 7.26 (dd, J=5.3, 6.9 Hz, 2H), 7.17 (d, J=6.9, 2H), 4.20 (t, J=7.2Hz, 2H), 3.23 (m, 2H), 2.66 (t, J=8.3 Hz, 2H), 2.57 (t, J=8.3 Hz, 2H),1.78 (m, 2H), 1.29 (m, 4H), 0.83 (m, 3H). LCMS calculated forC₂₂H₂₇BrN₇O₂ (M+H): 500. found: 500.1, 502.1.

Example 713-(7-bromo-5-oxo-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-3-yl)-N-(pyridin-4-ylmethyl)propanamidetrifluoroacetate

The title compound was prepared using procedures analogous to thosedescribed for Example 66. LCMS calculated for C₂₀H₂₄BrN₈O₂ (M+H): 487.1.found 487.1, 489.0.

Example 723-[2-(3-benzyl-1,2,4-oxadiazol-5-yl)ethyl]-7-bromo-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

3-(7-bromo-5-oxo-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-3-yl)propanoicacid (50 mg, 0.126 mmole) and CDI (21.8 mg, 0.139 mmole) were mixed inanhydrous DMF (4 ml). After stirring the solution for 3 hours at roomtemperature, benzylamidoxime (22.5 mg, 0.139 mmole) was added and thesolution heated at 90° C. for 20 hours, then at 110° C. for 4 hours.After evaporation of solvent, the residue was purified by preparativeLCMS to yield the desired product (8.2 mg, 12.7%). LCMS calculated forC₂₂H₂₄BrN₈O₂ (M+H): 511.1. found: 511.1, 513.1.

Example 737-bromo-9-pentyl-3-{2-[3-(2-thienylmethyl)-1,2,4-oxadiazol-5-yl]ethyl}-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 72. LCMS calculated for C₂₀H₂₂BrN₈O₂S (M+H):517.1. found 517.1, 519.1.

Example 747-bromo-9-pentyl-3-(2-{3-[4-(trifluoromethyl)benzyl]-1,2,4-oxadiazol-5-yl}ethyl)-6,9-dihydro-5H-pyrrolo[3,2-d][1,2,4]triazolo[4,3-a]pyrimidin-5-one

Step A: (1Z)—N′-hydroxy-2-[4-(trifluoromethyl)phenyl]ethanimidamide

A suspension of [4-(trifluoromethyl)phenyl]acetonitrile (1.0 g, 5.4mmoles), hydroxylamine hydrochloride (0.41 g, 5.9 mmoles) and NaHCO₃(0.50 g, 5.9 mmoles) in MeOH (15 ml) was refluxed for 4 hours. Thereaction mixture was then concentrated to remove the solvent methanol.The residue was extracted with ethyl acetate. The combined organiclayers were washed with brine and dried over Na₂SO₄ and concentrated toafford the desired product (1.0 g, 84.9%) as white solid. LCMScalculated for C₉H₁₀F₃N₂O (M+H): 219.1. found: 219.1.

Step B:7-bromo-9-pentyl-3-(2-3-[4-(trifluoromethyl)benzyl]-1,2,4-oxadiazol-5-ylethyl)-6,9-dihydro-5H-pyrrolo[3,2-d][1,2,4]triazolo[4,3-a]pyrimidin-5-one

3-(7-Bromo-5-oxo-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-3-yl)propanoicacid (100 mg, 0.252 mmole) and CDI (44.9 mg, 0.277 mmole) were dissolvedin anhydrous DMF (4 ml). After stirring the solution for 3 hours at roomtemperature, (1Z)—N′-hydroxy-2-[4-(trifluoromethyl)phenyl]ethanimidamide(60.4 mg, 0.277 mmole) was added and the solution heated at 90° C. for20 hours, then at 110° C. for 4 hours. After evaporation of solvent, theresidue was purified by preparative LC-MS to afford the desired product(6.4 mg, 4.4%) as white solid. LCMS calculated for C₂₄H₂₄BrF₃N₇O₂ (M+H):578.1. found 578.1, 580.1.

Example 757-bromo-3-{2-[3-(4-fluorobenzyl)-1,2,4-oxadiazol-5-yl]ethyl}-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 74. LCMS calculated for C₂₂H₂₂BrFN₈O₂ (M+H):529.1. found: 529.1, 531.1.

Example 767-bromo-9-pentyl-3-{2-[3-(4-methoxybenzyl)-1,2,4-oxadiazol-5-yl]ethyl}-6,9-dihydro-5H-pyrrolo[3,2-d][1,2,4]triazolo[4,3-a]pyrimidin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 74. LCMS calculated for C₂₃H₂₅BrN₈O₃ (M+H): 541.1.found 541.1, 543.1.

Example 777-bromo-9-pentyl-3-{2-[3-(pyridine-4-ylmethyl)-1,2,4-oxadiazol-5-yl]ethyl}-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 74. LCMS calculated for C₂₁H₂₂BrN₉O₂ (M+H): 512.1.found: 512.1, 514.1.

Example 787-bromo-9-pentyl-3-(2-{3-[3-(trifluoromethyl)benzyl]-1,2,4-oxadiazol-5-yl}ethyl)-6,9-dihydro-5H-pyrrolo[3,2-d][1,2,4]triazolo[4,3-a]pyrimidin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 74. LCMS calculated for C₂₄H₂₄BrF₃N₇O₂ (M+H):578.1. found 578.1, 580.1.

Example 797-bromo-9-pentyl-3-(2-{3-[2-(trifluoromethyl)benzyl]-1,2,4-oxadiazol-5-yl}ethyl)-6,9-dihydro-5H-pyrrolo[3,2-d][1,2,4]triazolo[4,3-a]pyrimidin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 74. LCMS calculated for C₂₄H₂₄BrF₃N₇O₂ (M+H):578.1. found 578.1, 580.1.

Example 807-bromo-9-pentyl-3-{2-[3-(pyridine-3-ylmethyl)-1,2,4-oxadiazol-5-yl]ethyl}-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-onetrifluoroacetate

The title compound was prepared using procedures analogous to thosedescribed for Example 74. LCMS calculated for C₂₁H₂₂BrN₉O₂ (M+H): 512.1.found: 512.1, 514.1.

Example 817-bromo-9-pentyl-3-{2-[3-(2-phenylethyl)-1,2,4-oxadiazol-5-yl]ethyl}-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 74. ¹HNMR (400 MHz, d₆-DMSO): δ 7.20 (m, 5H), 4.20(t, J=7.4 Hz, 2H), 3.67 (t, J=7.4 Hz, 2H), 3.41 (t, J=7.4 Hz, 4H), 3.35(br, 1H), 2.91 (s, 4H), 1.78 (m, 2H), 1.27 (m, 4H), 0.81 (m, 3H). LCMScalculated for C₂₃H₂₅BrN₈O₂ (M+H): 525.1. found: 525.1, 527.0.

Example 827-bromo-9-pentyl-3-{2-(3-phenyl-1,2,4-oxadiazol-5-yl)ethyl}-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 74. LCMS calculated for C₂₁H₂₁BrN₈O₂ (M+H): 497.1.found: 497.1, 499.1.

Example 837-bromo-3-{2-[3-(3-fluorobenzyl)-1,2,4-oxadiazol-5-yl]ethyl}-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 74. LCMS calculated for C₂₂H₂₂BrFN₈O₂ (M+H):529.1. found: 529.1, 531.1.

Example 847-bromo-3-{2-[3-(4-chlorobenzyl)-1,2,4-oxadiazol-5-yl]ethyl}-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 74. LCMS calculated for C₂₂H₂₂BrClN₈O₂ (M+H):545.1. found: 545.1, 547.1, 549.1.

Example 853-[2-(3-benzyl-1,2,4-oxadiazol-5-yl)ethyl]-7-chloro-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 72. LCMS calculated for C₂₂H₂₃ClN₈O₂ (M+H): 467.2.found: 467.2.

Example 867-bromo-3-{2-[3-(2-fluorobenzyl)-1,2,4-oxadiazol-5-yl]ethyl}-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 74. ¹HNMR (400 MHz, d₆-DMSO): δ 7.30 (m, 2H), 7.13(m, 2H), 4.19 (t, J=7.5 Hz, 2H), 4.05 (s, 2H), 3.64 (t, J=7.5 Hz, 2H),3.39 (t, J=7.5 Hz, 2H), 1.78 (m, 2H), 1.28 (m, 4H), 0.83 (m, 3H). LCMScalculated for C₂₂H₂₂BrFN₈O₂ (M+H): 529.1. found: 529.1, 531.1.

Example 877-bromo-3-{2-[3-(2-methoxybenzyl)-1,2,4-oxadiazol-5-yl]ethyl}-9-pentyl-6,9-dihydro-5H-pyrrolo[3,2-d][1,2,4]triazolo[4,3-a]pyrimidin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 74. LCMS calculated for C₂₃H₂₅BrN₈O₃ (M+H): 541.1.found 541.1, 543.1.

Example 887-bromo-3-[2-(3-ethyl-1,2,4-oxadiazol-5-yl)ethyl]-9-pentyl-6,9-dihydro-5H-pyrrolo[3,2-d][1,2,4]triazolo[4,3-a]pyrimidin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 72. LCMS calculated for C₁₇H₂₁BrN₈O₂ (M+H): 449.1.found 449.1.

Example 897-bromo-3-{2-[3-(3-methoxybenzyl)-1,2,4-oxadiazol-5-yl]ethyl}-9-pentyl-6,9-dihydro-5H-pyrrolo[3,2-d][1,2,4]triazolo[4,3-a]pyrimidin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 74. LCMS calculated for C₂₃H₂₅BrN₈O₃ (M+H): 541.1.found 541.1, 543.1.

Example 907-bromo-3-{2-[3-(3-methylbenzyl)-1,2,4-oxadiazol-5-yl]ethyl}-9-pentyl-6,9-dihydro-5H-pyrrolo[3,2-d][1,2,4]triazolo[4,3-a]pyrimidin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 74. LCMS calculated for C₂₃H₂₅BrN₈O₂ (M+H): 525.1.found 525.1, 527.1.

Example 917-bromo-3-{2-[3-(2,4-difluorobenzyl)-1,2,4-oxadiazol-5-yl]ethyl}-9-pentyl-6,9-dihydro-5H-pyrrolo[3,2-d][1,2,4]triazolo[4,3-a]pyrimidin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 74. LCMS calculated for C₂₂H₂₁BrF2N₈O₂ (M+H):547.1. found 547.1, 549.1.

Example 927-bromo-3-{2-[3-(3,5-difluorobenzyl)-1,2,4-oxadiazol-5-yl]ethyl}-9-pentyl-6,9-dihydro-5H-pyrrolo[3,2-d][1,2,4]triazolo[4,3-a]pyrimidin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 74. LCMS calculated for C₂₂H₂₁BrF2N₈O₂ (M+H):547.1. found 547.1, 549.1.

Example 937-bromo-9-pentyl-3-{2-[3-(3-thienylmethyl)-1,2,4-oxadiazol-5-yl]ethyl}-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 74. LCMS calculated for C₂₀H₂₂BrN₈O₂S (M+H):517.1. found 517.1, 519.1.

Example 947-bromo-9-pentyl-3-{2-[3-(1-phenylcyclopropyl)-1,2,4-oxadiazol-5-yl]ethyl}-6,9-dihydro-5H-pyrrolo[3,2-d][1,2,4]triazolo[4,3-a]pyrimidin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 72. LCMS calculated for C₂₄H₂₅BrN₈O₂ (M+H): 537.1.found 537.1, 539.1.

Example 957-bromo-9-pentyl-3-{2-[3-(pyridine-2-ylmethyl)-1,2,4-oxadiazol-5-yl]ethyl}-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-onetrifluoroacetate

The title compound was prepared using procedures analogous to thosedescribed for Example 74. LCMS calculated for C₂₁H₂₂BrN₉O₂ (M+H): 512.1.found: 512.1, 514.1.

Example 963-[(2R)-2-(3-benzyl-1,2,4-oxadiazol-5-yl)propyl]-7-bromo-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 74. LCMS calculated for C₂₃H₂₅BrN₈O₂ (M+H): 525.1.found: 525.1, 527.1.

Example 977-bromo-3-(2-{3-[(4-methyl-1,3-thiazol-2-yl)methyl]-1,2,4-oxadiazol-5-yl}ethyl)-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 74. LCMS calculated for C₂₀H₂₃BrN₉O₂S (M+H):532.1. found: 532.0, 534.0.

Example 987-bromo-3-{2-[3-(2-methylbenzyl)-1,2,4-oxadiazol-5-yl]ethyl}-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 74. LCMS calculated for C₂₃H₂₆BrN₈O₂ (M+H): 525.1.found 525.0, 527.0.

Example 997-bromo-3-(2-{3-[hydroxy(phenyl)methyl]-1,2,4-oxadiazol-5-yl}ethyl)-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 74. LCMS calculated for C₂₂H₂₄BrN₈O₃ (M+H): 527.1.found 527.0, 529.0.

Example 1007-bromo-3-{2-[3-(2,5-difluorobenzyl)-1,2,4-oxadiazol-5-yl]ethyl}-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 74. LCMS calculated for C₂₂H₂₂BrF₂N₈O₂ (M+H):547.1. found: 547.0, 547.0.

Example 1017-bromo-9-pentyl-3-{2-[3-(pyrimidin-5-ylmethyl)-1,2,4-oxadiazol-5-yl]ethyl}-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 74. ¹HNMR (400 MHz, d₆-DMSO): δ 9.06 (s, 1H), 8.74(s, 2H), 4.20 (t, J=7.6 Hz, 2H), 4.15 (s, 2H), 3.66 (t, J=7.6 Hz, 2H),3.41 (t, J=7.6 Hz, 2H), 1.78 (m, 2H), 1.29 (m, 4H), 0.83 (m, 3H). LCMScalculated for C₂₀H₂₂BrN₁₀O₂ (M+H): 513.1. found: 513.1, 515.1.

Example 1027-bromo-9-butyl-3-{2-[3-(2-fluorobenzyl)-1,2,4-oxadiazol-5-yl]ethyl}-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 74. LCMS calculated for C₂₁H₂₁BrFN₈O₂ (M+H):515.1. found 515.0, 517.0.

Example 1033-[2-(3-benzyl-1,2,4-oxadiazol-5-yl)ethyl]-9-pentyl-7-(trifluoromethyl)-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

Step A: methyl 3-(3-benzyl-1,2,4-oxadiazol-5-yl)propanoate

Butanedioic acid, monomethyl ester (4.0 g, 30.3 mmole) and CDI (5.40 g,33.3 mmole) were dissolved in anhydrous DMF (15 ml). After stirring thesolution at room temperature for 3 hours,(1Z)—N′-hydroxy-2-phenylethanimidamide (5.0 g, 33.3 mmole) was added andthe solution heated at 90° C. for 20 hours. After evaporation ofsolvent, the residue was dissolved in EtOAc. The organic phase waswashed with water and brine, dried over Na2SO4. After filtration andevaporation of solvent, the residue was purified by flash chromatographyon silica gel eluted with EtOAc/Hexane (25/75). The purification gave5.2 g (69.7%) of product as light yellowish oil. LCMS calculated forC₁₃H₁₅N₂O₃ (M+H): 247.1. found 247.0.

Step B: 3-(3-benzyl-1,2,4-oxadiazol-5-yl)propanoic acid

To a solution of methyl 3-(3-benzyl-1,2,4-oxadiazol-5-yl)propanoate (5.2g, 21.1 mmole) in methanol (30 ml) was added 50 ml of 1N NaOH. Themixture was stirred at room temperature for 2 hours. The mixture wasadjusted to PH=3-4 under ice bath, and extracted with EtOAc (3×). Thecombined organic phases were washed with water and brine, dried overNa₂SO₄ and concentrated to yield the desired product (4.8 g, 98%) ascolorless oil. LCMS calculated for C₁₂H₁₃N₂O₃ (M+H): 233.1. found 233.0.

Step C:3-(3-benzyl-1,2,4-oxadiazol-5-yl)-N′-[(2E)-6-oxo-3-pentyl-8-(trifluoromethyl)-1,3,6,7-tetrahydro-2H-purin-2-ylidene]propanohydrazide

The mixture of 3-(3-benzyl-1,2,4-oxadiazol-5-yl)propanoic acid (100.0mg, 0.431 mmole),(2E)-3-pentyl-8-(trifluoromethyl)-3,7-dihydro-1H-purine-2,6-dione2-hydrazone (144.1 mg, 0.474 mmole), BOP (209.5 mg, 0.474 mmole) andtriethylamine (0.120 ml, 0.861 mmole). in DMF (4 ml) was stirred at roomtemperature overnight. The mixture was diluted with EtOAc (100 ml) andwashed with water, then brine. The organic phase was dried over Na₂SO₄,filtrated and concentrated to give the desired product (220.1 mg, 98.6%)as yellowish oil. LCMS calculated for C₂₃H₂₆F₃N₈O₃ (M+H): m/z=5192.found 519.2.

Step D:3-[2-(3-benzyl-1,2,4-oxadiazol-5-yl)ethyl]-9-pentyl-7-(trifluoromethyl)-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The mixture of3-(3-benzyl-1,2,4-oxodiazol-5-yl)-N′-[(2E)-6-oxo-3-pentyl-8-(trifluoromethyl)-1,3,6,7-tetrahydro-2H-purin-2-ylidene]propanohydrazide(220.1 mg, 0.424 mmole) in toluene (20 ml) was refluxed for 5 hours.After evaporation of solvent, the residue was purified by preparativeLCMS to yield the desired product (37.9 mg, 17.8%) as white solid. LCMScalculated for C₂₃H₂₄F₃N₈O₂ (M+H): 501.2. found 501.1.

Example 1043-[2-(3-benzyl-1,2,4-oxadiazol-5-yl)ethyl]-7-cyclopropyl-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 103. LCMS calculated for C₂₅H₂₉N₈O₂ (M+H): 473.2.found: 473.1

Example 1053-methyl-9-pentyl-7-[1-(trifluoromethyl)cyclopropyl]-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 32. ¹HNMR (400 MHz, d₆-DMSO): δ 4.22 (t, J=7.03Hz, 2H), 2.71 (s, 4H), 1.80 (m, 2H), 1.49 (s, 3H), 1.28 (m, 4H), 0.81(m, 3H). LCMS calculated for C₁₆H₂₀F₃N₆O (M+H): 369.2. found: 269.1

Example 1067-(2,2-difluorocyclopropyl)-3-methyl-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 32. LCMS calculated for C₁₅H₁₉F₂N₆O (M+H): 337.2.found: 337.1.

Example 1077-(1-hydroxycyclopropyl)-3-methyl-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 32. LCMS calculated for C₁₅H₂₁N₆O₂ (M+H): 317.2.found: 317.1.

Example 1087-bromo-9-pentyl-3-[2-(5-phenyl-1,3,4-oxadiazol-2-yl)ethyl]-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

Step A: methyl 4-(2-benzoylhydrazino)-4-oxobutanoate

The mixture of benzhydrazide (1.5 g, 11.0 mmol), butanedioic acid,monomethyl ester (2.0 g, 15 mmol),benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(5.4 g, 12 mmol), N,N-diisopropylethylamine (3.8 mL, 22 mmol) and4-dimethylaminopyridine (0.87 g, 7.2 mmol) in DMF (30 mL) was stirred atroom temperature overnight. The mixture was quenched with water andextracted with ethyl acetate three times. The combined organic layerswere washed by brine, dried over sodium sulfate, filtered andconcentrated. The crude residue was purified by flash columnchromatography to yield the desired product (900 mg, 32.6%). LCMScalculated for C₁₂H₁₅N₂O₄ (M+H): 251.1. found: 251.1.

Step B: Methyl 3-(5-phenyl-1,3,4-oxadiazol-2-yl)propanoate

Thionyl chloride (0.34 mL, 4.7 mmol) was added to the mixture of methyl4-(2-benzoylhydrazino)-4-oxobutanoate (900 mg, 4 mmol), Pyridine (0.87mL, 0.011 mol) in tetrahydrofuran (20 mL) at room temperature. Afterstirring for 3 hours, the reaction mixture was concentrated. The residuewas mixed with toluene (20 mL) and refluxed overnight. The reaction wasdiluted with water and extracted with ethyl acetate three times. Thecombined organic layers were dried with sodium sulfate, filtered, andconcentrated in vacuo. The residue was purified by flash columnchromatography to yield the desired product (600 mg, 72%). LCMScalculated for C₁₂H₁₃N₂O₃ (M+H): 233.1. found: 233.1.

Step C: 3-(5-phenyl-1,3,4-oxadiazol-2-yl)propanoic acid

A mixture of methyl 3-(5-phenyl-1,3,4-oxadiazol-2-yl)propanoate (600 mg,2.0 mmol) in 1 M of aqueous NaOH (10 mL) and Methanol (10 mL) wasstirred at room temperature overnight. The reaction solution wasadjusted to pH 5 and extracted with ethyl acetate three times. Thecombined organic layers were dried, filtered and concentrated to yieldthe desired product (0.50 g, 83%). LCMS calculated for C₁₁H₁₁N₂O₃ (M+H):219.1. found 219.1.

Step D:N′-[(2E)-6-oxo-3-pentyl-1,3,6,7-tetrahydro-2H-purin-2-ylidene]-3-(5-phenyl-1,3,4-oxadiazol-2-yl)propanohydrazide

The mixture of 3-(5-phenyl-1,3,4-oxadiazol-2-yl)propanoic acid (500 mg,20 mmol), (2E)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione 2-hydrazone (480mg, 0.0020 mol), benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate (980 mg, 22 mmol), 4-dimethylaminopyridine (100 mg,10 mmol), and N,N-diisopropylethylamine (0.73 mL, 42 mmol) in DMF (30mL) was stirred at room temperature overnight. The mixture was quenchedwith water and extracted with ethyl acetate three times. The combinedorganic layers were washed by brine, dried over sodium sulfate, filteredand concentrated. The crude residue was purified by flash columnchromatography to yield the desired product (485 mg, 48.5%). LCMScalculated for C₂₁H₂₅N₈O₃ (M+H): 437.2. found 437.2.

Step E:9-pentyl-3-[2-(5-phenyl-1,3,4-oxadiazol-2-yl)ethyl]-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The mixture ofN′-[(2E)-6-oxo-3-pentyl-1,3,6,7-tetrahydro-2H-purin-2-ylidene]-3-(5-phenyl-1,3,4-oxadiazol-2-yl)propanohydrazide(485 mg, 1.11 mmol) in toluene (50 mL) was heated to reflux overnight.The mixture was concentrated to yield the desired product (310 mg,66.7%). LCMS calculated for C₂₁H₂₃N₈O₂ (M+H): 419.2. found 419.2.

Step F:7-bromo-9-pentyl-3-[2-(5-phenyl-1,3,4-oxadiazol-2-yl)ethyl]-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The mixture of9-pentyl-3-[2-(5-phenyl-1,3,4-oxadiazol-2-yl)ethyl]-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one(53 mg, 0.13 mmol) and N-bromosuccinimide (34 mg, 0.19 mmol) in THF (20mL) was stirred at 70° C. for 1 hour. The reaction mixture wasconcentrated and the residue was purified by preparative LCMS to givethe desired product. LCMS calculated for C₂₁H₂₂BrN₈O₂ (M+H): 497.1.found: 497.1.

Example 1093-[2-(5-benzyl-1,3,4-oxadiazol-2-yl)ethyl]-7-bromo-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 108. ¹HNMR (300 MHz, CD₃OD): δ 8.18 (d, J=7.2 Hz,1H), 7.3 (m, 4H), 4.34 (m, 2H), 3.78 (m, 2H), 3.64 (m, 2H), 3.52 (m,2H), 1.89 (m, 2H), 1.39 (m, 4H), 0.92 (m, 3H). LCMS calculated forC₂₂H₂₄BrN₈O₂ (M+H): 511.1. found: 511.1, 513.1.

Example 110N-[(7-bromo-5-oxo-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-3-yl)methyl]benzamide

Step A: benzyl2-oxo-2-[(2E)-2-(6-oxo-3-pentyl-1,3,6,7-tetrahydro-2H-purin-2-ylidene)hydrazino]ethylcarbamate

The mixture of (2E)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione 2-hydrazone(0.50 g, 0.0021 mol), N-carbobenzyloxyglycine (0.49 g, 0.0023 mol),benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate(1.0 g, 2.3 mmol) and triethylamine (0.59 mL, 0.0042 mol) in DMF (20 mL)was stirred at room temperature overnight. The reaction mixture wasdiluted with EtOAc and washed with water (4×) and brine (lx). Theaqueous was extracted with EtOAc (2×). The combined organic layers weredried (MgSO₄) and concentrated to give the desired product (1.30 g,86%). LCMS calculated for C₂₀H₂₆N₇O₄ (M+H): 428.2. found 428.2.

Step B: benzyl[(5-oxo-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-3-yl)methyl]carbamate

The solution of benzyl2-oxo-2-[(2E)-2-(6-oxo-3-pentyl-1,3,6,7-tetrahydro-2H-purin-2-ylidene)hydrazino]ethylcarbamate(0.60 g, 0.84 mmol) in toluene (30 mL) was refluxed overnight.M+H=410.1. The product was precipitated from the reaction mixture andfiltered to give the desired product (300 mg, 87%). LCMS calculated forC₂₀H₂₄N₇O₃ (M+H): 410.2. found: 410.2.

Step C:3-(aminomethyl)-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-onehydrochloride

To the solution of benzyl[(5-oxo-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-3-yl)methyl]carbamate(0.30 g, 0.73 mmol) in methanol (20 mL) and 1 mL of conc. HCl was added10% Pd/C under N₂. The mixture was shaken under 30 PSI H₂ for 3 hours.The reaction mixture was filtered through celite and concentrated toyield the desired product (210 mg, 92%). LCMS calculated for C₁₂H₁₈N₁₇O(M+H): 276.2. found: 276.2.

Step D:N-[(5-oxo-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-3-yl)methyl]benzamide

The mixture of3-(aminomethyl)-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-onehydrochloride (160 mg, 0.51 mmol), [B] benzoic Acid (0.069 g, 0.56mmol), benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate (0.25 g, 0.56 mmol) and triethylamine (0.21 mL, 1.5mmol) in DMF (10 mL) was stirred at room temperature overnight. Thereaction mixture was purified by preparative LCMS to yield the desiredproduct (150 mg, 77%). LCMS calculated for C₁₉H₂₂N₇O₂ (M+H): 380.2.found: 380.2.

Step E:N-[(7-bromo-5-oxo-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-3-yl)methyl]benzamide

To the solution ofN-[(5-oxo-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-3-yl)methyl]benzamide(0.11 g, 0.28 mmol) in THF (10 mL) was added N-Bromosuccinimide (0.076g, 0.42 mmol). The mixture was stirred at 70° C. for 1 hour. Thereaction mixture was concentrated and purified by preparative LCMS. LCMScalculated for C₁₉H₂₁BrN₇O₂ (M+H): 458.1. found: 458.0, 460.0.

Example 111N-[(7-bromo-5-oxo-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-3-yl)methyl]acetamide

The title compound was prepared using procedures analogous to thosedescribed for Example 108. LCMS calculated for C₁₄H₁₉BrN₇O₂ (M+H):396.1. found: 396.0, 398.0.

Example 1123-(1-benzoylpiperidin-4-yl)-7-bromo-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 108. LCMS calculated for C₂₃H₂₇BrN₇O₂ (M+H):512.1. found: 512.1, 514.1.

Example 1133-[3-(3-benzyl-1,2,4-oxadiazol-5-yl)propyl]-7-bromo-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for example 72. ¹HNMR (300 MHz, CD₃OD): δ 7.24 (m, 5H), 4.31(t, J=6.8 Hz, 2H), 3.97 (s, 2H), 3.40 (t, J=6.8 Hz, 2H), 3.03 (t, J=6.8Hz, 2H), 2.33 (m, 2H), 1.88 (m, 2H), 1.40 (m, 4H), 0.92 (m, 3H). LCMScalculated for C₂₃H₂₆BrN₈O₂ (M+H): 525.1. found: 525.1, 527.1.

Example 1142-bromo-4-pentyl-1,4-dihydro-9H-[1,2,4]triazolo[1,5-a]purin-9-one

Step A: 2-(methylthio)-3-pentyl-3,7-dihydro-6H-purin-6-one

To a solution of 3-pentyl-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one(13.0 g, 54.6 mmol) in 2 M of sodium hydroxide in water (250 mL) wasadded dimethyl sulfate (6.2 mL, 66 mmol), and the reaction mixture wasstirred at room temperature for 1 hour, then neutralized with aceticacid. The precipitate was collected by filtration and recrystallizedfrom ethyl acetate-MeOH (1:1) to give the desired product (5.50 g, 40%).LCMS calculated for C₁₁H₁₇N₄OS (M+H): 253.1. found: 253.1.

Step B: 2-amino-3-pentyl-3,7-dihydro-6H-purin-6-one

2-(Methylthio)-3-pentyl-3,7-dihydro-6H-purin-6-one (5.0 g, 0.020 mol)was mixed with 100 ml of 28% ammonia hydroxide in a seal tube. Themixture was stirred at 100° C. for 4 days. After cooling to roomtemperature, the solid was filtered and dried to yield the desiredproduct (3.0 g, 68%). LCMS calculated for C₁₀H₁₆N₅O (M+H): 222.1. found:222.1.

Step C: 1-amino-2-imino-3-pentyl-1,2,3,7-tetrahydro-6H-purin-6-one

A solution of 2-imino-3-pentyl-1,2,3,7-tetrahydro-6 h-purin-6-one (750mg, 3.39 mmol) and 18 m of hydrazine in water (30 ml) was stirred at150° C. for 30 min on a microwave reactor. The reaction was diluted withwater and extracted with ethyl acetate three times, dried with sodiumsulfate, filtered, and concentrated in vacuo to yield the crude productfor next step without further purification. LCMS calculated forC₁₀H₁₇N₆O (M+H): 237.1. found: 237.2.

Step D: 4-pentyl-1,4-dihydro-9H-[1,2,4]triazolo[1,5-a]purin-9-one

The mixture of1-amino-2-imino-3-pentyl-1,2,3,7-tetrahydro-6H-purin-6-one (0.10 g, 0.4mmol) and ethyl orthoformate (5 mL, 30 mmol) was stirred at 100° C. for6 hours. The reaction mixture was concentrated and purified bypreparative LCMS to yield the desired product (20 mg, 20%). LCMScalculated for C₁₁H₁₅N₆O (M+H): 247.1. found: 247.1.

Step E:2-bromo-4-pentyl-1,4-dihydro-9H-[1,2,4]triazolo[1,5-a]purin-9-one

To the mixture of4-pentyl-1,4-dihydro-9H-[1,2,4]triazolo[1,5-a]purin-9-one (19 mg, 0.077mmol) in tetrahydrofuran (10 mL) was added N-bromosuccinimide (20 mg,0.12 mol) at rt. The mixture was stirred at 70° C. for 1 hour. Themixture was concentrated and purified by preparative LCMS to yield thedesired product (3.10 mg, 12.4%). LCMS calculated for C₁₁H₁₄BrN₆O (M+H):325.0. found: 325.0, 327.0.

Example 1153-methyl-9-pentyl-7-(1,3-thiazol-4-yl)-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 32. LCMS calculated for C₁₅H₁₈N₇OS (M+H): 344.1.found: 344.1

Example 1167-bromo-9-pentyl-3-[2-(3-pyrazin-2-yl-1,2,4-oxadiazol-5-yl)ethyl]-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-onetrifluoroacetate

The title compound was prepared using procedures analogous to thosedescribed for Example 72. ¹HNMR (300 MHz, d₆-DMSO): δ 8.78 (d, J=1.9 Hz,1H), 8.36 (dd, J=1.9, 5.0 Hz, 1H), 7.62 (dd, J=1.9, 8.2 Hz, 1H), 4.21(t, J=7.1 Hz, 2H), 3.77 (t, J=7.1 Hz, 2H), 3.56 (t, J=7.1 Hz, 2H), 1.79(m, 2H), 1.29 (m, 4H), 0.83 (m, 3H). LCMS calculated for C₁₉H₁₉BrN₁₀O₂(M+H): 499.1. found: 499.1

Example 1177-bromo-9-pentyl-3-[2-(3-pyridin-3-yl-1,2,4-oxadiazol-5-yl)ethyl]-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-onetrifluoroacetate

The title compound was prepared using procedures analogous to thosedescribed for Example 72. ¹HNMR (300 MHz, CD₃OD): δ 9.27 (s, 1H), 8.75(m, 2H), 4.33 (t, J=8.1 Hz, 2H), 3.92 (t, J=8.1 Hz, 2H), 3.64 (t, J=8.1Hz, 2H), 1.89 (m, 2H), 1.39 (m, 4H), 0.90 (m, 3H). LCMS calculated forC₂₀H₂₀BrN₉O₂ (M+H): 498.1. found: 498.1

Example 1187-bromo-9-pentyl-3-[2-(3-pyridin-2-yl-1,2,4-oxadiazol-5-yl)ethyl]-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-onetrifluoroacetate

The title compound was prepared using procedures analogous to thosedescribed for Example 72. ¹HNMR (300 MHz, d₆-DMSO): δ 8.68 (S, 1H), 7.95(m, 2H), 7.53 (m, 2H), 4.15 (m, 2H), 3.72 (m, 2H), 3.50 (m, 2H), 1.74(m, 2H), 1.24 (m, 4H), 0.78 (m, 3H). LCMS calculated for C₂₀H₂₀BrN₉O₂(M+H): 498.1. found: 498.1

Example 1197-bromo-9-pentyl-3-[2-(3-pyridin-4-yl-1,2,4-oxadiazol-5-yl)ethyl]-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-onetrifluoroacetate

The title compound was prepared using procedures analogous to thosedescribed for Example 72. ¹HNMR (300 MHz, d₆-DMSO): δ 8.77 (d, J=5.5 Hz,2H), 7.89 (d, J=5.5 Hz, 2H), 4.20 (t, J=8.3 Hz, 2H), 3.77 (t, J=8.3 Hz,2H), 3.56 (t, J=8.3 Hz, 2H), 1.78 (m, 2H), 1.28 (m, 4H), 0.82 (m, 3H).LCMS calculated for C₂₀H₂₀BrN₉O₂ (M+H): 498.1. found: 498.1

Example 1207-bromo-9-pentyl-3-{2-[3-(2-thienyl)-1,2,4-oxadiazol-5-yl)ethyl]-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 72. ¹HNMR (300 MHz, d₆-DMSO): δ 7.85 (dd, J=1.3,5.0 Hz, 1H), 7.74 (dd, J=1.3, 4.0 Hz, 1H), 7.22 (dd, J=5.0, 4.0 Hz, 1H),4.20 (t, J=6.8 Hz, 2H), 3.73 (t, J=6.8 Hz, 2H), 3.49 (t, J=6.8 Hz, 2H),1.79 (m, 2H), 1.28 (m, 4H), 0.82 (m, 3H). LCMS calculated forC₁₉H₁₉BrN₈O₂S (M+H): 503.1. found: 503.1.

Example 1213-(1,3-benzodioxol-5-ylmethyl)-7-bromo-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 35. ¹HNMR (400 MHz, CD₃OD): δ 6.83 (s, 1H), 6.78(dd, J=2.1, 7.5 Hz, 1H), 6.70 (dd, J=2.1, 7.5 Hz, 1H), 4.53 (s, 2H),4.31 (m, 2H), 1.88 (m, 2H), 1.28 (m, 4H), 0.90 (m, 3H). LCMS calculatedfor C₁₉H₁₉BrN₆O₃ (M+H): 458.1. found: 459.1, 461.1.

Example 1227-bromo-9-pentyl-3-pyrimidin-5-yl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for Example 16. ¹HNMR (300 MHz, d₆-DMSO): δ 9.27 (s, 1H), 9.11(s, 2H), 4.34 (t, J=6.9 Hz, 2H), 3.38 (br, 1H), 1.87 (m, 2H), 1.34 (m,4H), 0.87 (m, 3H). LCMS calculated for C₁₅H₁₅BrN₈O (M+H): 403.1. found:403.1, 405.1.

Example 1237-bromo-9-pentyl-3-[3-(3-phenyl-1,2,4-oxadiazol-5-yl)propyl]-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

Step A: methyl 4-(3-phenyl-1,2,4-oxadiazol-5-yl)butanoate

Pentanedioic acid, monomethyl ester (1.00 g, 6.84 mmole) and CDI (1.22g, 7.53 mmole) were dissolved in anhydrous DMF (10 ml). After stirringat room temperature for 3 hours, (1Z)—N′-hydroxybenzenecarboximidamide(1.02 g, 7.53 mmole) was added and the solution heated at 90° C. for 20h. After evaporation of solvent, the residue was diluted with ethylacetate. The organic layer was washed with water and brine, dried overNa₂SO₄, filtered and concentrated to give the desired product (1.53 g,91% yield). LCMS calculated for C₁₃H₁₅N₂O₃ (M+H): 247.1. found: 247.1.

Step B: 4-(3-phenyl-1,2,4-oxadiazol-5-yl)butanoic acid

To a solution of methyl 3-(3-phenyl-1,2,4-oxadiazol-5-yl)butanoate (1.53g, 6.21 mmole) in methanol (10 ml) was added 1N NaOH (10 mL). Afterstirring at room temperature for 2 hours, the reaction solution wasacidified to pH=3-4 with 6N HCl under an ice bath and then extractedwith ethyl acetate three times. The combined organic layers were washedwith water and then brine, dried over Na₂SO₄, filtered and concentratedto give the desired product (1.44 g, 99% yield) as white solid. LCMScalculated for C₁₂H₁₃N₂O₃ (M+H): 233.1. found: 233.1.

Step C:N′-[(2E)-6-oxo-3-pentyl-1,3,6,7-tetrahydro-2H-purin-2-ylidene]-4-(3-phenyl-1,2,4-oxadiazol-5-yl)butanohydrazide

A mixture of 4-(3-phenyl-1,2,4-oxadiazol-5-yl)butanoic acid (1.44 g,6.20 mmol), (2e)-3-pentyl-3,7-dihydro-1 h-purine-2,6-dione 2-hydrazone(1.61 g, 6.82 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate (3.02 g, 6.82 mmol) and triethylamine (1.73 ml, 12.4mmol) in DMF (30 ml) was stirred at room temperature overnight. Thereaction was diluted with water and extracted with ethyl acetate (3×).The organic layer was washed with water and then brine, dried overNa₂SO₄, filtered and concentrated to give the desired product (2.78 g,99% yield) as yellowish oil. LCMS calculated for C₂₂H₂₇N₈O₃ (M+H):451.2. found: 451.1.

Step D:9-pentyl-3-[3-(3-phenyl-1,2,4-oxadiazol-5-yl)propyl]-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The mixture ofN′-[(2E)-6-oxo-3-pentyl-1,3,6,7-tetrahydro-2H-purin-2-ylidene]-4-(3-phenyl-1,2,4-oxadiazol-5-yl)butanohydrazide(2.78 g, 6.17 mmol) in toluene (100 ml) was refluxed for 2 hours. Aftercooling to room temperature, the solid was filtered, washed with ethylacetate/Hexane (1:9) and dried to give the desired product (1.97 g, 74%yield). LCMS calculated for C₂₂H₂₅N₈O₂ (M+H): 433.2. found: 433.1.

Step E:7-bromo-9-pentyl-3-[3-(3-phenyl-1,2,4-oxadiazol-5-yl)propyl]-6,9-dihydro-5H-[1,2,4]triazolo[4,3-c]purin-5-one

To the solution of9-pentyl-3-[3-(3-phenyl-1,2,4-oxadiazol-5-yl)propyl]-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one(0.50 g, 1.16 mmole) in THF (125 ml) at room temperature was addedN-bromosuccinimide (0.309 g, 1.73 mmole). The mixture was stirred at 70°C. for 1 h. The mixture was concentrated and purified by preparativeLCMS to yield the desired product (122 mg, 21% yield). LCMS calculatedfor C₂₂H₂₄BrN₈O₂ (M+H): 511.1. found: 511.0.

Example 1247-bromo-9-pentyl-3-[3-(3-pyridin-2-yl-1,2,4-oxadiazol-5-yl)propyl]-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-onetrifluoroacetate

The title compound was prepared using procedures analogous to thosedescribed for example 123. LCMS calculated for C₂₁H₂₂BrN₉O₂ (M+H):511.1, 513.1. found: 511.1, 513.1.

Example 1257-bromo-9-pentyl-3-[3-(3-pyridin-3-yl-1,2,4-oxadiazol-5-yl)propyl]-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-onetrifluoroacetate

The title compound was prepared using procedures analogous to thosedescribed for example 123. LCMS calculated for C₂₁H₂₂BrN₉O₂ (M+H):511.1, 513.1. found: 511.1, 513.1.

Example 1267-bromo-9-pentyl-3-[3-(3-pyridin-4-yl-1,2,4-oxadiazol-5-yl)propyl]-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-onetrifluoroacetate

The title compound was prepared using procedures analogous to thosedescribed for example 123. LCMS calculated for C₂₁H₂₂BrN₉O₂ (M+H):511.1, 513.1. found: 511.1, 513.1.

Example 1277-bromo-9-pentyl-3-[3-(3-pyrazin-2-yl-1,2,4-oxadiazol-5-yl)propyl]-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-onetrifluoroacetate

The title compound was prepared using procedures analogous to thosedescribed for example 123. LCMS calculated for C₂₀H_(2i)BrN₁₀O₂ (M+H):513.1, 515.1. found: 513.1, 515.1.

Example 1287-bromo-9-pentyl-3-{3-[3-(2-thienyl)-1,2,4-oxadiazol-5-yl]propyl}-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for example 123. LCMS calculated for C₂₀H₂₁BrN₈O₂S (M+H):517.1, 519.1. found: 517.1, 519.1.

Example 1297-bromo-9-pentyl-3-{3-[3-(3-thienyl)-1,2,4-oxadiazol-5-yl]propyl}-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for example 123. LCMS calculated for C₂₀H₂₁BrN₈O₂S (M+H):517.1, 519.1. found: 517.1, 519.1.

Example 1307-bromo-9-pentyl-3-(3-{3-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}propyl)-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for example 123. LCMS calculated for C₂₃H₂₂BrF₃N₈O₂ (M+H):579.1, 581.1. found: 579.1, 581.1.

Example 1317-bromo-3-{3-[3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl]propyl}-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for example 123. LCMS calculated for C₂₃H₂₅BrN₈O₃ (M+H):541.1, 543.1. found: 541.1, 543.1.

Example 1327-bromo-3-{3-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]propyl}-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for example 123. LCMS calculated for C₂₂H₂₂BrFN₈O₂ (M+H):529.1, 531.1. found: 529.1, 531.1.

Example 1337-bromo-9-pentyl-3-[3-(3-pyrimidin-2-yl-1,2,4-oxadiazol-5-yl)propyl]-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-onetrifluoroacetate

The title compound was prepared using procedures analogous to thosedescribed for example 123. LCMS calculated for C₂₀H_(2i)BrN₁₀O₂ (M+H):513.1, 515.1. found: 513.1, 515.1.

Example 1347-bromo-3-{3-[3-(2-methoxyphenyl)-1,2,4-oxadiazol-5-yl]propyl}-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for example 123. LCMS calculated for C₂₃H₂₅BrN₈O₃ (M+H):541.1, 543.1. found: 541.1, 543.1.

Example 1357-bromo-3-{3-[3-(3-methoxyphenyl)-1,2,4-oxadiazol-5-yl]propyl}-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for example 123. LCMS calculated for C₂₃H₂₅BrN₈O₃ (M+H):541.1, 543.1. found: 541.1, 543.1.

Example 1367-bromo-3-{3-[3-(4-ethynylphenyl)-1,2,4-oxadiazol-5-yl]propyl}-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for example 123. LCMS calculated for C₂₄H₂₃BrN₈O₂ (M+H):535.1, 537.1. found: 535.1, 537.1.

Example 1377-bromo-3-{3-[3-(1H-indol-5-yl)-1,2,4-oxadiazol-5-yl]propyl}-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-onetrifluoroacetate

The title compound was prepared using procedures analogous to thosedescribed for example 123. LCMS calculated for C₂₄H₂₄BrN₉O₂ (M+H):550.1, 552.1. found: 550.1, 552.1.

Example 1387-bromo-3-{3-[3-(1H-indol-3-yl)-1,2,4-oxadiazol-5-yl]propyl}-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-onetrifluoroacetate

The title compound was prepared using procedures analogous to thosedescribed for example 123. LCMS calculated for C₂₄H₂₄BrN₉O₂ (M+H):550.1, 552.1. found: 550.1, 552.1.

Example 1397-bromo-3-{3-[3-(6-methoxypyridin-3-yl)-1,2,4-oxadiazol-5-yl]propyl}-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-onetrifluoroacetate

The title compound was prepared using procedures analogous to thosedescribed for example 123. LCMS calculated for C₂₂H₂₄BrN₉O₃ (M+H):542.1, 544.1. found: 542.1, 544.1.

Example 1403-{3-[3-(4-aminopyrimidin-5-yl)-1,2,4-oxadiazol-5-yl]propyl}-7-bromo-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-onetrifluoroacetate

The title compound was prepared using procedures analogous to thosedescribed for example 123. LCMS calculated for C₂₀H₂₂BrN₁₁O₂ (M+H):528.1, 530.1. found: 528.1, 530.1.

Example 1417-bromo-3-3-[3-(4-hydroxyphenyl)-1,2,4-oxadiazol-5-yl]propyl-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

To a solution of7-bromo-3-3-[3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl]propyl-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one(23.4 mg, 0.043 mmole) in CH₂Cl₂ (5 ml) at 0° C. was added a solution ofBBr₃ in CH₂Cl₂ (1 M, 0.43 ml, 0.43 mmole). The mixture was stirred atroom temperature overnight. The reaction was quenched with H₂O at 0° C.The reaction mixture was extracted with CH₂Cl₂ (3×). The combinedorganic layers were washed with water and then brine, dried over Na₂SO₄,filtered and concentrated to give the crude product, which was purifiedby preparative LCMS to yield the desired product (2.9 mg, 13% yield) aswhite solid. LCMS calculated for C₂₂H₂₄BrN₈O₃ (M+H): 527.1, 529.1.found: 527.0, 529.0.

Example 1427-bromo-3-3-[3-(2-hydroxyphenyl)-1,2,4-oxadiazol-5-yl]propyl-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for example 141. LCMS calculated for C₂₂H₂₄BrN₈O₃ (M+H):527.1, 529.1. found: 527.0, 529.0.

Example 1437-bromo-3-3-[3-(3-hydroxyphenyl)-1,2,4-oxadiazol-5-yl]propyl-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for example 141. LCMS calculated for C₂₂H₂₄BrN₈O₃ (M+H):527.1, 529.1. found: 527.0, 529.0.

Example 1447-bromo-3-{2-[3-(4-hydroxybenzyl)-1,2,4-oxadiazol-5-yl]ethyl}-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for example 141. LCMS calculated for C₂₂H₂₄BrN₈O₃ (M+H):527.1, 529.1. found: 527.0, 529.0.

Example 1457-bromo-3-{2-[3-(2-hydroxybenzyl)-1,2,4-oxadiazol-5-yl]ethyl}-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for example 141. LCMS calculated for C₂₂H₂₄BrN₈O₃ (M+H):527.1, 529.1. found: 527.0, 529.0.

Example 1467-bromo-3-{2-[3-(3-hydroxybenzyl)-1,2,4-oxadiazol-5-yl]ethyl}-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for example 141. LCMS calculated for C₂₂H₂₄BrN₈O₃ (M+H):527.1, 529.1. found: 527.0, 529.0.

Example 1477-bromo-9-pentyl-3-[3-(4-phenyl-1H-pyrazol-1-yl)propyl]-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

Step A: ethyl 4-(4-phenyl-M-pyrazol-1-yl)butanoate

The mixture of ethyl 4-bromobutyrate (0.400 g, 2.05 mmole),4-phenyl-1H-pyrazole (0.296 g, 2.05 mmole) and K₂CO₃ (0.567 g, 4.10mmole) in DMF (10 ml) was stirred at room temperature overnight. Thereaction mixture was diluted with water (100 ml) and extracted withethyl acetate (2×). The combined organic phases were washed with waterand then brine, dried over Na₂SO₄, filtered and concentrated to give thecrude product, which was purified by preparative to afford the desiredproduct (73 mg, 52%) as colorless oil. LCMS calculated for C₁₅H₁₉N₂O₂(M+H): 259. found: 259.1.

Step B: 4-(4-phenyl-1H-pyrazol-1-yl)butanoic acid

A mixture of ethyl 4-(4-phenyl-1H-pyrazo-1yl)butanoate (273 mg, 1.06mmole) in methanol (5 ml) and 1N NaOH (5 mL) was stirred at roomtemperature for 2 hours. The reaction mixture was adjusted to be acidic(pH=3-4) with 6 N HCl with an ice bath and then extracted with EtOAc(3×). The combined organic phases were washed with water and brine,dried over Na₂SO₄, filtered and concentrated to give the desired product(190 mg, 78%). LCMS calculated for C₁₃H₁₅N₂O₂ (M+H): 231.1. found:231.1.

Step C:N′-[(2E)-6-oxo-3-pentyl-1,3,6,7-tetrahydro-2H-purin-2-ylidene]-4-(4-phenyl-1H-pyrazol-1-yl)butanohydrazide

A mixture of 4-(4-phenyl-1H-pyrazol-1-yl)butanoic acid (190 mg, 0.825mmol), (2E)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione 2-hydrazone (195.0mg, 0.825 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate (401 mg, 0.908 mmol) and triethyl amine (0.23 ml,1.65 mmol) in DMF (10 ml) was stirred at room temperature overnight. Themixture was diluted with EtOAc and washed with water and then brine. Theorganic phase was dried over Na₂SO₄, filtered and concentrated to yieldthe desired product (369 mg, 99.7% yield) as yellowish oil. LCMScalculated for C₂₃H₂₉N₈O₂ (M+H): 449.2. found: 449.2.

Step D:9-pentyl-3-[3-(4-phenyl-1H-pyrazol-1-yl)propyl]-6,9-dihydro-5H-[1,2,4]triazolo[4,3-c]purin-5-one

A mixture ofN′-[(2E)-6-oxo-3-pentyl-1,3,6,7-tetrahydro-2H-purin-2-ylidene]-4-(4-phenyl-1H-pyrazol-1-yl)butanohydrazide(369 mg, 0.823 mmols) in toluene (20 ml) was refluxed for 2 hours. Aftercooling to room temperature, the solid formed was filtered, washed withEtOAc/Hexane (1:9) and dried to give the desired product (234 mg, 66%yield) as off pink solid. LCMS calculated for C₂₃H₂₇N₈O (M+H): 431.2.found: 431.1.

Step E:7-bromo-9-pentyl-3-[3-(4-phenyl-1H-pyrazol-1-yl)propyl]-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

To a solution of9-pentyl-3-[3-(4-phenyl-1H-pyrazol-1-yl)propyl]-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one(234 mg, 0.543 mmol) in THF (45 ml) at room temperature was addedN-bromosuccinimide (145 mg, 0.814 mmol). After stirring at 70° C. for 1hour, the reaction mixture was concentrated and then purified bypreparative LCMS to give the desired product (106 mg, 38%) as whitesolid. LCMS calculated for C₂₃H₂₆BrN₈O (M+H): 509.1, 511.1. found:509.0, 511.1.

Example 1487-bromo-9-pentyl-3-[3-(4-phenyl-1H-imidazol-1-yl)propyl]-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for example 147. LCMS calculated for C₂₃H₂₆BrN₈O (M+H): 509.1,511.1. found: 509.0, 511.1.

Example 1497-bromo-3-3-[4-(5-fluoro-2-hydroxyphenyl)-1H-pyrazol-1-yl]propyl-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for example 147. LCMS calculated for C₂₃H₂₅BrFN₈O₂ (M+H):543.1. found: 543.0, 545.0.

Example 1507-bromo-3-2-[5-(4-methoxyphenyl)-1,2,4-oxadiazol-3-yl]ethyl-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

Step A: 4,4-diethoxy-N-hydroxybutanimidamide

A mixture of 4,4-diethoxybutanenitrile (5.0 g, 32 mmol), hydroxylaminehydrochloride (2.4 g, 35 mmol) and sodium bicarbonate (2.9 g, 35 mmol)in methanol (50 mL) was refluxed for 5 hours. After cooling to roomtemperature, the reaction mixture was concentrated and the residue wasdiluted with EtOAc and water. The water layer was extracted with EtOAc(2×). The combined organic layers were washed with water, dried overNa₂SO₄, filtered and concentrated to give the product, which was usednext step without purification. ¹HNMR (300 MHz, CD₃Cl): δ 4.73 (br, 1H),4.51 (t, J=5.5 Hz, 1H), 3.66 (m, 2H), 3.50 (m, 2H), 2.21 (t, J=8.2 Hz,2H), 1.86 9 m, 2H), 1.19 (t, J=8.2 Hz, 6H).

Step B: 3-(3,3-diethoxypropyl)-5-(4-methoxyphenyl)-1,2,4-oxadiazole

A mixture of 4-methoxybenzoic acid (0.88 g, 5.78 mmol) and CDI (1.02 g,6.31 mmol) in DMF (20 ml) was stirred at room temperature for 3 hours.4-diethoxy-N-hydroxybutanimidamide (1.0 g, 5.26 mmol) was added to theabove mixture and then heated at 100° C. overnight. After cooling toroom temperature, the reaction mixture was diluted with water andextracted with EtOAc (3×). The combined organic layers was dried overNa2SO4, filtered, and concentrated in vacuo to yield the desired productLCMS calculated for C₁₆H₂₃N₂O₄ (M+H): 307.2. found: 307.2.

Step C: 3-[5-(4-methoxyphenyl)-1,2,4-oxadiazol-3-yl]propanal

A mixture of 3-(3,3-diethoxypropyl)-5-(4-methoxyphenyl)-1,2,4-oxadiazole(1.0 g, 3.0 mmol) in 2N HCl (10 mL) and THF (10 mL) was stirred at roomtemperature overnight. The reaction mixture was extracted with EtOAc(3×). The organic layers were washed with water, dried over Na₂SO₄,filtered and concentrated to give the desired product. LCMS calculatedfor C₁₂H₁₃N₂O₃ (M+H): 233.1. found: 233.1.

Step D:3-2-[5-(4-methoxyphenyl)-1,2,4-oxadiazol-3-yl]ethyl-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

A mixture of 1H-purine-2,6-dione 2-hydrazone (680 mg, 2.88 mmol) and3-[5-(4-methoxyphenyl)-1,2,4-oxadiazol-3-yl]propanal (900 mg, 3.88 mol)in ethanol (20 mL) was refluxed for 4 hours. The reaction mixture wasconcentrated and the residue was mixed with acetic acid (10 mL). Theresulting mixture was refluxed for 3 hours. The reaction mixture wasconcentrated and then diluted with water and extracted with EtOAc (3×).The combined organic layers was dried over Na₂SO₄, filtered,concentrated and purified by preparative LCMS to give the desiredproduct (830 mg, 64% yield). LCMS calculated for C₂₂H₂₅N₈O₃ (M+H):449.2. found: 449.2.

Step E:7-bromo-3-2-[5-(4-methoxyphenyl)-1,2,4-oxadiazol-3-yl]ethyl-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-c]purin-5-one

To a solution of3-2-[5-(4-methoxyphenyl)-1,2,4-oxadiazol-3-yl]ethyl-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one(160 mg, 0.36 mol) in DMF (15 mL) at room temperature was addedN-bromosuccinimide (110 mg, 0.61 mol). After stirring at 70° C. for 1hour, the reaction mixture was concentrated and purified by preparativeLCMS to provide the desired product. LCMS calculated for C₂₂H₂₄BrN₈O₃(M+H): 527.1, 529.0. found: 527.0, 529.0.

Example 1517-bromo-3-2-[5-(4-hydroxyphenyl)-1,2,4-oxadiazol-3-yl]ethyl-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

To a solution of7-bromo-3-2-[5-(4-methoxyphenyl)-1,2,4-oxadiazol-3-yl]ethyl-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one(190 mg, 0.36 mmol) in CH₂Cl₂ (12 mL) was added a solution of BBr₃ inCH₂Cl₂ (1 M, 7.0 ml, 7.0 mmole) at room temperature. After stirring atroom temperature overnight, the reaction mixture was concentrated andpurified by preparative LCMS to give the desired product. LCMScalculated for C₂₁H₂₂BrN₈O₃ (M+H): 513.1, 515.1. found: 513.1, 515.1.

Example 1527-bromo-3-2-[5-(3-methoxyphenyl)-1,2,4-oxadiazol-3-yl]ethyl-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for example 152. LCMS calculated for C₂₂H₂₄BrN₈O₃ (M+H):527.1, 529.0. found: 527.0, 529.0.

Example 1537-bromo-3-2-[5-(3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl]ethyl-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for example 151. LCMS calculated for C₂₁H₂₂BrN₈O₃ (M+H):513.1, 515.1. found: 513.1, 515.1.

Example 1547-bromo-3-2-[5-(2-methoxyphenyl)-1,2,4-oxadiazol-3-yl]ethyl-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for example 150. LCMS calculated for C₂₂H₂₄BrN₈O₃ (M+H):527.1, 529.0. found: 527.0, 529.0.

Example 1557-bromo-3-2-[5-(2-hydroxyphenyl)-1,2,4-oxadiazol-3-yl]ethyl-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for example 151. LCMS calculated for C₂₁H₂₂BrN₈O₃ (M+H):513.1, 515.1. found: 513.1, 515.1.

Example 1567-bromo-3-2-[5-(2-chloro-4-methoxyphenyl)-1,2,4-oxadiazol-3-yl]ethyl-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for example 150. LCMS calculated for C₂₂H₂₃BrClN₈O₃ (M+H):561.1, 563.1. found: 561.1, 563.1.

Example 1577-bromo-3-2-[5-(2-chloro-4-hydroxyphenyl)-1,2,4-oxadiazol-3-yl]ethyl-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for example 151. LCMS calculated for C₂₁H₂₁BrClN₈O₃ (M+H):547.1, 549.1. found: 547.0, 549.0.

Example 1587-bromo-9-pentyl-3-[2-(5-pyridin-4-yl-1,2,4-oxadiazol-3-yl)ethyl]-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-onetrifluoroacetate

The title compound was prepared using procedures analogous to thosedescribed for example 150. LCMS calculated for C₂₀H₂₁BrN₉O₂ (M+H):498.1, 500.1. found: 498.1, 500.1.

Example 1597-bromo-9-pentyl-3-[2-(5-pyridin-3-yl-1,2,4-oxadiazol-3-yl)ethyl]-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-onetrifluoroacetate

The title compound was prepared using procedures analogous to thosedescribed for example 150. LCMS calculated for C₂₀H₂₁BrN₉O₂ (M+H):498.1, 500.1. found: 498.1, 500.1.

Example 1607-bromo-9-pentyl-3-[2-(5-pyridin-2-yl-1,2,4-oxadiazol-3-yl)ethyl]-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-onetrifluoroacetate

The title compound was prepared using procedures analogous to thosedescribed for example 150. LCMS calculated for C₂₀H₂₁BrN₉O₂ (M+H):498.1, 500.1. found: 498.1, 500.1.

Example 1617-bromo-3-{2-[3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl]ethyl}-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for example 72. LCMS calculated for C₂₂H₂₄BrN₈O₃ (M+H): 527.1,529.0. found: 527.0, 529.0.

Example 1627-bromo-3-{2-[3-(3-methoxyphenyl)-1,2,4-oxadiazol-5-yl]ethyl}-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for example 72. LCMS calculated for C₂₂H₂₄BrN₈O₃ (M+H): 527.1,529.0. found: 527.0, 529.0.

Example 1637-bromo-3-{2-[3-(2-methoxyphenyl)-1,2,4-oxadiazol-5-yl]ethyl}-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for example 72. LCMS calculated for C₂₂H₂₄BrN₈O₃ (M+H): 527.1,529.0. found: 527.0, 529.0.

Example 1647-bromo-3-{2-[3-(4-hydroxyphenyl)-1,2,4-oxadiazol-5-yl]ethyl}-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for example 141. LCMS calculated for C₂₁H_(2i)BrN₈O₃ (M+H):512.1, 514.1. found: 512.0, 514.0.

Example 1657-bromo-3-{2-[3-(3-hydroxyphenyl)-1,2,4-oxadiazol-5-yl]ethyl}-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for example 141. LCMS calculated for C₂₁H₂₁BrN₈O₃ (M+H):512.1, 514.1. found: 512.0, 514.0.

Example 1667-bromo-3-{2-[3-(2-hydroxyphenyl)-1,2,4-oxadiazol-5-yl]ethyl}-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for example 141. LCMS calculated for C₂₁H_(2i)BrN₈O₃ (M+H):512.1, 514.1. found: 512.0, 514.0.

Example 1677-bromo-3-{2-[3-(2-chloro-4-methoxyphenyl)-1,2,4-oxadiazol-5-yl]ethyl}-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for example 72. LCMS calculated for C₂₂H₂₃BrClN₈O₃ (M+H):561.1, 563.1. found: 561.1, 563.1.

Example 1687-bromo-3-{2-[3-(2-chloro-hydroxyphenyl)-1,2,4-oxadiazol-5-yl]ethyl}-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for example 141. LCMS calculated for C₂₁H₂₁BrClN₈O₃ (M+H):547.1, 549.1. found: 547.0, 549.0.

Example 1693-[2-(5-benzyl-1,2,4-oxadiazol-3-yl)ethyl]-7-bromo-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for example 150. LCMS calculated for C₂₂H₂₃BrN₈O₂ (M+H):511.1, 513.1. found: 511.0, 513.0.

Example 1707-bromo-3-{3-[3-(2-chloro-4-methoxyphenyl)-1,2,4-oxadiazol-5-yl]propyl}-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for example 123. LCMS calculated for C₂₃H₂₅BrClN₈O₃ (M+H):575.1, 577.1. found: 575.1, 577.1.

Example 1717-bromo-3-{3-[3-(2-chloro-4-hydroxyphenyl)-1,2,4-oxadiazol-5-yl]propyl}-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for example 141. LCMS calculated for C₂₂H₂₃BrClN₈O₃ (M+H):561.1, 563.1. found: 561.1, 563.1.

Example 172N-[2-(7-bromo-5-oxo-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-3-yl)ethyl]-4-methoxybenzamide

Step A: benzyl(3Z)-3-[(2E)-(6-oxo-3-pentyl-1,3,6,7-tetrahydro-2H-purin-2-ylidene)hydrazono]propylcarbamate

A mixture of (2E)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione 2-hydrazone(2.3 g, 9.6 mmol) and benzyl (3-oxopropyl)carbamate (2.0 g, 9.6 mol) inethanol (30 mL) was refluxed overnight. The reaction mixture wasconcentrated to give the product (4.0 g, 58% yield), which was used fornext step without further purification. LCMS calculated for C₂₁H₂₈N₇O₃(M+H): 426.2. found: 426.1.

Step B: benzyl[2-(5-oxo-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-3-yl)ethyl]carbamate

A mixture of benzyl(3Z)-3-[(2E)-(6-oxo-3-pentyl-1,3,6,7-tetrahydro-2H-purin-2-ylidene)hydrazono]propylcarbamate(4.0 g, 5.6 mol) in acetic acid (50 mLl) was refluxed in the airovernight. The mixture was concentrated and purified by preparative LCMSto give the desired product (1.3 g, 54% yield) as a white solid. LCMScalculated for C₂₁H₂₆N₇O₃ (M+H): 424.2. found: 424.2.

Step C:3-(2-aminoethyl)-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

To a solution of benzyl[2-(5-oxo-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-3-yl)ethyl]carbamate(0.52 g, 1.2 mmol) in methanol (50 mL) was added 10% Pd/C (100 mg). Thereaction mixture was shaken in a hydrogenation reactor under 50 Psi H₂for 3 hours. The reaction mixture was filtered through a pad of celite.The filtrate was concentrated to give the desired product (320 mg, 90%yield). LCMS calculated for C₁₃H₂₀N₇O (M+H): 290.2. found: 290.1.

Step D:3-(2-aminoethyl)-7-bromo-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

To a mixture of3-(2-aminoethyl)-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one(310 mg, 1.1 mmol) in THF (50 mL), was added N-Bromosuccinimide (0.29 g,1.6 mol). The mixture was stirred at 70° C. for 1 hour. The reactionmixture was concentrated. The solid was filtered and washed with EtOActo yield the desired product (300 mg, 76% yield). LCMS calculated forC₁₃H₁₉BrN₇O (M+H): 368.1, 370.1. found: 368.0, 370.0.

Step E:N-[2-(7-bromo-5-oxo-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-3-yl)ethyl]-4-methoxybenzamide

A mixture of3-(2-aminoethyl)-7-bromo-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one(70 mg, 0.20 mmol), 4-methoxybenzoic acid (32 mg, 0.21 mmol),benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(92 mg, 0.21 mmol), and triethylamine (0.053 mL, 0.38 mmol) in DMF (5mL) was stirred at room temperature overnight. The reaction mixture wasdiluted with water and acetonitrile and then purified by prep LCMS togive the desired product (70 mg, 73% yield). LCMS calculated forC₂₁H₂₅BrN₇O₃ (M+H): 502.1, 504.0. found: 502.0, 504.0.

Example 173N-[2-(7-bromo-5-oxo-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-3-yl)ethyl]benzamide

The title compound was prepared using procedures analogous to thosedescribed for example 172. LCMS calculated for C₂₀H₂₃BrN₇O₂ (M+H):472.1; 474.1. found: 472.0, 474.0.

Example 174N-[2-(7-bromo-5-oxo-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-3-yl)ethyl]isonicotinamidetrifluoroacetate

The title compound was prepared using procedures analogous to thosedescribed for example 172. LCMS calculated for C₁₈H₂₂BrN₈O₂ (M+H):473.1; 475.1. found: 473.0, 475.0.

Example 1757-bromo-9-pentyl-3-[2-(pyrimidin-2-ylamino)ethyl]-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-onetrifluoroacetate

A mixture of3-(2-aminoethyl)-7-bromo-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one(60 mg, 0.20 mmol), 2-chloropyrimidine (25 mg, 0.22 mmol) andtriethylamine (0.045 mL, 0.32 mmol) in 1,4-Dioxane (10 mL) was refluxedovernight. The reaction mixture was concentrated, and the residue waspurified by preparative LCMS to give the desired product. LCMScalculated for C₁₇H₂₁BrN₉O: 446.1. found: 446.0, 448.0.

Example 176 N-[2-(7-bromo-5-oxo-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-3-yl)ethyl]nicotinamide trifluoroacetate

The title compound was prepared using procedures analogous to thosedescribed for example 172. LCMS calculated for C₁₈H₂₂BrN₈O₂ (M+H):473.1; 475.1. found: 473.0, 475.0.

Example 177 N-[2-(7-bromo-5-oxo-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-3-yl)ethyl]pyridine-2-carboxamide trifluoroacetate

To a solution of 2-Pyridinecarboxylic acid (20 mg, 0.16 mmol) in DMF (5mL) was added CDI (26 mg, 0.16 mmol). After stirring at room temperaturefor 2 hours,3-(2-aminoethyl)-7-bromo-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one(50 mg, 0.0001 mol) was added the above solution, and the resultingmixture was stirred at room temperature overnight. The reaction mixturewas diluted with water and acetonitrile and then purified by preparativeLCMS to give the desired product. LCMS calculated for C₁₉H₂₂BrN₈O₂(M+H): 473.1, 475.1. found: 473.0, 475.0.

Example 1783-amino-N-[2-(7-bromo-5-oxo-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-3-yl)ethyl]isonicotinamidetrifluoroacetate

The title compound was prepared using procedures analogous to thosedescribed for example 172. LCMS calculated for C₁₉H₂₃BrN₉O₂ (M+H):488.1; 490.1. found: 488.0, 490.0.

Example 179 N-[2-(7-bromo-5-oxo-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-3-yl)ethyl]-2-methylisonicotinamidetrifluoroacetate

The title compound was prepared using procedures analogous to thosedescribed for example 177. LCMS calculated for C₂₀H₂₄BrN₈O₂ (M+H):487.1; 489.1. found: 487.0, 489.0.

Example 180N-[2-(7-bromo-5-oxo-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-3-yl)ethyl]-M-phenylurea

A mixture of3-(2-aminoethyl)-7-bromo-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one(62 mg, 0.17 mmol) and phenyl isocyanate (0.018 mL, 0.16 mmol) in DMF (5mL) was stirred at room temperature overnight. The reaction mixture wasdiluted with water and acetonitrile and then purified by preparativeLCMS to give the desired product (about 80% conversion). LCMS calculatedfor C₂₀H₂₄BrN₈O₂ (M+H): 487.1; 489.1. found: 487.0, 489.0.

Example 181N-[2-(7-bromo-5-oxo-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-3-yl)ethyl]-4-hydroxybenzamide

To a solution ofN-[2-(7-bromo-5-oxo-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-3-yl)ethyl]-4-methoxybenzamide(63.0 mg, 0.125 mmol) in CH₂Cl₂ (5 mL) at 0° C. was added a solution ofBoron tribromide in CH₂Cl₂ (1.0 M, 1.3 mL, 1.3 mmol). The mixture wasstirred at room temperature overnight. The reaction mixture was quenchedwith water and then concentrated and purified by preparative LCMS togive the desired product. LCMS calculated for C₂₀H₂₃BrN₇O₃ (M+H):m/z=488.1, 490.1. found: 488.0, 489.9.

Example 1823-methyl-7-(pentafluoroethyl)-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for example 1. LCMS calculated for C₁₄H₁₆F₅N₆O (M+H): 379.1.found: 379.1.

Example 183 Preparation of7-bromo-3-methyl-9-(4,4,4-trifluorobutyl)-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for example 5. LCMS calculated for C₁₁H₁₁BrF₃N₆O (M+H): 379.0,381.0.0. found: 379.0, 381.0.

Example 184 Preparation of7-bromo-3-methyl-9-(5,5,5-trifluoropentyl)-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for example 5. LCMS calculated for C₁₂H₁₃BrF₃N₆O (M+H): 393.0,395.0. found: 393.0, 395.0.

Example 185 Preparation of7-bromo-9-(4-fluorobutyl)-3-methyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for example 5. LCMS calculated for C₁₁H₁₃BrFN₆O (M+H): 343.0.found: 343.0.

Example 186 Preparation of7-bromo-9-(4-fluoropentyl)-3-methyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one

The title compound was prepared using procedures analogous to thosedescribed for example 5. LCMS calculated for C₁₂H₁₅BrFN₆O (M+H): 357.0,359.0. found: 357.0, 359.0.

Example A GTPγS Recruitment Assay

Membranes were prepared from HEK293 cells transiently transfected withhuman HM74a and G_(α0) protein. Assays were performed in 384-well formatin a volume of 50 μL per assay point. Serial dilutions of compounds wereprepared in the assay buffer (20 mM HEPES pH. 7.4, 100 mM NaCl, 10 mMMgCl₂, 10 mg/L saponin and 10 μM GDP) and mixed with membranes (2 μg perassay point) and ³⁵S GTPγS (Amersham, 0.3 nM) in the assay buffer. Themixtures were incubated at room temperature for 30 mM and wheat germagglutinin SPA beads (Amersham) (0.2 mg per assay point) in the assaybuffer were added. After 30 mM incubation with agitation, plates werecentrifuged at 1500 g for 5 mM and bound ³⁵S GTPγS was determined bycounting on a TopCount scintillation counter. An active compoundaccording to this assay has an EC₅₀ of about 50 μM or less. In someembodiments, the compounds of the present invention have an EC₅₀ of lessthan about 50 μM, less than about 40 μM, less than about 30 μM, lessthan about 20 μM, less than about 10 μM, less than about 5 μM, less thanabout 1 μM, less than about 500 nM, less than 300 nM, or less than about200 nM. For example, the compound of Example 1 has an EC₅₀ of 80 nM inthis assay.

Example B Nicotinic Acid Displacement Assay

Membranes were prepared from HEK293 cells transiently transfected withthe human HM74a and G_(α0) protein. Wheat germ agglutinin SPA beads(Amersham) were weighed and suspended in the assay buffer (50 mMTris-HCl, pH. 7.5, 1 mM MgCl₂ and 0.02% CHAPS). The beads were mixedwith membrane (75 μg membrane/mg beads) at room temperature for 1 hr.The beads were spun down and washed once with buffer and thenresuspended in buffer at 5 mg beads/ml. 20 nM of ³H nicotinic acid wasadded to the beads and then mixed with compounds at (total vol. of 50μL). Nonspecific binding was determined by the inclusion of 100 μMnicotinic acid. The binding mixtures were incubated at room temperaturefor overnight with agitation. Plates were centrifuged at 1500 g for 5 mMand bound ³H nicotinic acid was determined by counting on a TopCountscintillation counter. An active compound according to this assay has anIC₅₀ of about 50 μM or less. In some embodiments, the compounds of thepresent invention have an IC₅₀ of less than about 50 μM, less than about40 μM, less than about 30 μM, less than about 20 μM, less than about 10μM, less than about 5 μM, less than about 1 μM, less than about 500 nM,less than 300 nM, or less than about 200 nM.

Example C FLIPR Assay

HEK293e cells transfected with human HM74a and G_(α16) DNA were seededthe day before the assay at 50,000 cells/well in 384-well plates. Cellswere washed once with 1×HBSS and incubated with FLIPR Calcium 3(Molecular Devices) dye in 1×HBSS buffer containing 3 mM probenecid at37° C. and 5% CO₂ for 60 mM Compounds were added to the cell plate andfluorescence changes due to G_(α10)-mediated intracellular calciumresponse were measured. An active compound according to this assay hasan EC₅₀ of about 50 μM or less. In some embodiments, the compounds ofthe present invention have an EC₅₀ of less than about 50 μM, less thanabout 40 μM, less than about 30 μM, less than about 20 μM, less thanabout 10 μM, less than about 5 μM, less than about 1 μM, less than about500 nM, less than 300 nM, or less than about 200 nM.

Example D cAMP Assay

CHO cells stably transfected with human HM74a were seeded at 7,500cells/well in a 96-well plate in HAMS F12 medium with 10% FBS. The platewas incubated overnight at 37° C. and 5% CO₂. The test compounds wereprepared in a stimulation buffer containing 1× HANKS, 20 mM HEPES, 5 μMforskolin, and 0.25 mM IBMX. The media from the cell plate was removedbefore adding 30 μL of the test compounds. After 30 minute incubation at37° C. and 5% CO₂, the cAMP level was assayed using HitHunter cAMP XSassay kit (DiscoverX, CA). IC₅₀ determinations were based on compoundinhibition relative to DMSO controls. An active compound according tothis assay has an IC₅₀ of about 100 μM or less. In some embodiments, thecompounds of the present invention have an IC₅₀ of less than about 100μM, less than about 80 μM, less than about 60 μM, less than about 40 μM,less than about 30 μM, less than about 20 μM, less than about 10 μM,less than about 5 μM, less than about 1 μM, less than about 500 nM, lessthan 300 nM, or less than about 200 nM. For example, the compound ofExample 1 has an IC₅₀ of 20 nM in this assay.

Example E Adipocyte Lipolysis Assay

Preadipocytes purchased from Zen Bio were plated at 8.7×10⁴ cells/wellin 96-well plates, differentiated for 14 days and mature adipocytesassayed during days 15 through 21. Adipocyte maturation is assessed bythe presence of rounded cells with large lipid droplets in thecytoplasm. Following maturation, cells were washed and incubatedovernight with IBMX (100 μM) and various concentrations of compounddiluted in assay buffer containing a final DMSO concentration of 0.1%.After overnight culture, the glycerol concentration in the supernatantswas determined with the Lipolysis Assay Kit purchased from Zen-Bio.Absorbance at 540 nm is directly proportional to the glycerolconcentration in the sample. IC₅₀ determinations were based on compoundinhibition relative to DMSO controls. An active compound according tothis assay has an IC₅₀ of about 10 μM or less. In some embodiments, thecompounds of the present invention have an IC₅₀ of less than about 10μM, less than about 5 μM, less than about 2 μM, less than about 1 μM,less than about 500 nM, less than 300 nM, less than 200 nM, less than100 nM, or less than about 50 nM. For example, the compound of Example77 has an IC₅₀ of 37 nM in this assay.

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including all patent,patent applications, and publications, cited in the present applicationis incorporated herein by reference in its entirety.

What is claimed is:
 1. A compound of Formula I:

or pharmaceutically acceptable salt or prodrug thereof, wherein: adashed line indicates an optional bond; X is N, CR^(3a), CR^(4a)R^(5a),or NR^(6a); Y is N, CR^(3b), CR^(4b)R^(5b), or NR^(6b); L is —(C₁₋₆alkylene)-(Q¹)_(m)-(C₁₋₆ alkylene)_(p)-(Q²)_(q)-(C₁₋₆ alkylene)_(r)-,optionally substituted with 1, 2, 3, 4, or 5 R^(L1), wherein if m and qare both 1, then p is 1; R¹ is H, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, or Cy, wherein said C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, or C₂₋₁₀alkynyl is optionally substituted with 1, 2, 3, 4, or 5 R^(L2); R² ishalo, cyano, C₁₋₃ haloalkyl, Z, SR^(A), or a moiety having the formula:

R^(3a) and R^(3b) are independently selected from H, halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, C₁₋₆cyanoalkyl, Cy¹, CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d),C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a), S(O)R^(b), S(O)NR^(c)R^(d),S(O)₂R^(b), NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d), wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl is optionally substituted with 1,2, or 3 substitutents independently selected from Cy¹, CN, NO₂, halo,OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d),NR^(c)C(O)OR^(a), S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b),NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d); R^(4a), R^(4b), R^(5a), andR^(5b) are independently selected from H, halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, C₁₋₆cyanoalkyl, Cy², CN, NO₂, OR^(a1), SR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1),NR^(c1)R^(d1), NR^(c1)C(O)R^(b1), NR^(c1)C(O)NR^(c1)R^(d1),NR^(c1)C(O)OR^(a1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1),NR^(c1)S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1), wherein said C₁₋₆ alkyl,C₂₋₆ alkenyl, and C₂₋₆ alkynyl are optionally substituted with 1, 2, or3 substitutents independently selected from Cy², CN, NO₂, OR^(a1),SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1),OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)C(O)OR^(a1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), NR^(c1)S(O)₂R^(b1), andS(O)₂NR^(c1)R^(d1); R^(6a) and R^(6b) are independently selected from H,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, Cy², C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), S(O)R^(b1), S(O)NR^(c1)R^(d1),S(O)₂R^(b1), NR^(c1)S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1), wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are optionally substitutedwith 1, 2, or 3 substitutents independently selected from Cy², CN, NO₂,OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)C(O)OR^(a1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), NR^(a)S(O)₂R^(b1), andS(O)₂NR^(c1)R^(d1); R^(L1) and R^(L2) are independently selected fromhalo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂,OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2),OC(O)R^(b2), OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)C(O)OR^(a2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2), andS(O)₂NR^(c2)R^(d2); R^(2a) is H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₁₀alkynyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, C₁₋₆ cyanoalkyl, Cy⁴, CN,NO₂, C(O)R^(b6), C(O)NR^(c6)R^(d6), or C(O)OR^(a6); Cy is aryl,heteroaryl, cycloalkyl, and heterocycloalkyl, each optionallysubstituted with 1, 2, 3, 4 or 5 substituents selected from halo, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, CN, NO₂, OR^(a3),SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3),OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3), andS(O)₂NR^(c3)R^(d3); Cy¹ and Cy² are independently selected from aryl,heteroaryl, cycloalkyl, and heterocycloalkyl, each optionallysubstituted with 1, 2, 3, 4 or 5 substituents selected from halo, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, CN, NO₂, OR^(a4),SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4),OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4),S(O)₂NR^(c4)R^(d4), and Cy³, wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, orC₂₋₄ alkynyl is optionally substituted with 1, 2, or 3 substituentsindependently selected from CN, NO₂, halo, OR^(a4), SR^(a4), C(O)R^(b4),C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4),NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4), S(O)R^(b4),S(O)NR^(c4)R^(d4), S(O)₂R^(b4), S(O)₂NR^(c4)R^(d4), and Cy³; Cy³ and Cy⁴are independently selected from aryl, heteroaryl, cycloalkyl, andheterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5substituents selected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₁₋₄ haloalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, CN, NO₂,OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6),OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)OR^(a6), S(O)R^(b6), S(O)NR^(c6)R^(d6), S(O)₂R^(b6), andS(O)₂NR^(c6)R^(d6); Z is aryl, heteroaryl, cycloalkyl, andheterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5substituents selected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₁₋₄ haloalkyl, CN, NO₂, OR^(a6), SR^(a6), C(O)R^(b6),C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6), OC(O)NR^(c6)R^(d6),NR^(c6)R^(d6), NR^(c6)C(O)R^(b6), NR^(c6)C(O)OR^(a6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), and S(O)₂NR^(c6)R^(d6); R^(A) is H orC₁₋₄ alkyl; Q¹ and Q² are independently selected from O, S, NH, CH₂, CO,CS, SO, SO₂, OCH₂, SCH₂, NHCH₂, CH₂CH₂, COCH₂, CONH, COO, SOCH₂, SONH,SO₂CH₂, and SO₂NH; R^(a) and R^(a1) are independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and Cy², whereinsaid C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl, isoptionally substituted with 1, 2, 3, 4, or 5 substituents selected fromhalo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆hydroxyalkyl, C₁₋₆ cyanoalkyl, Cy², CN, NO₂, OR^(a5), SR^(a5),C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5),OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5), S(O)R^(b5),S(O)NR^(c5)R^(d5), S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5), andS(O)₂NR^(c5)R^(d5); R^(a2), R^(a3), R^(a4), R^(a5), and R^(a6) areindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein saidC₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted withOH, cyano, amino, halo, C₁₋₆ alkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, cycloalkyl or heterocycloalkyl; R^(b) and R^(b1) areindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and Cy², wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, or C₂₋₆ alkynyl, is optionally substituted with 1, 2, 3, 4, or5 substituents selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, C₁₋₆ cyanoalkyl, Cy², CN,NO₂, OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5),OC(O)R^(b5), OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5), S(O)R^(b5),S(O)NR^(c5)R^(d5), S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5), andS(O)₂NR^(c5)R^(d5); R^(b2), R^(b3), R^(b4), R^(b5), and R^(b6) areindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein saidC₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted withOH, cyano, amino, halo, C₁₋₆ alkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, cycloalkyl or heterocycloalkyl; R^(c) and R^(d) areindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and Cy², wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, or C₂₋₆ alkynyl, is optionally substituted with 1, 2, 3, 4, or5 substituents independently selected from halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, C₁₋₆cyanoalkyl, Cy², CN, NO₂, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), NR^(c5)C(O)NR^(c5)R^(d5),NR^(c5)C(O)OR^(a5), S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5),NR^(c5)S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5); or R^(c) and R^(d) togetherwith the N atom to which they are attached form a 4-, 5-, 6- or7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3substituents independently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, C₁₋₆ cyanoalkyl, Cy²,CN, NO₂, OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5),OC(O)R^(b5), OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5), S(O)R^(b5),S(O)NR^(c5)R^(d5), S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5), andS(O)₂NR^(c5)R^(d5); R^(c1) and R^(d1) are independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and Cy², whereinsaid C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl, isoptionally substituted with 1, 2, 3, 4, or 5 substituents independentlyselected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₁₋₆ hydroxyalkyl, C₁₋₆ cyanoalkyl, Cy², CN, NO₂, OR^(a5),SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5),OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5), S(O)R^(b5),S(O)NR^(c5)R^(d5), S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5), andS(O)₂NR^(c5)R^(d5); or R^(c1) and R^(d1) together with the N atom towhich they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 substituents independentlyselected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₁₋₆ hydroxyalkyl, C₁₋₆ cyanoalkyl, Cy², CN, NO₂, OR^(a5),SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5),OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5), S(O)R^(b5),S(O)NR^(c5)R^(d5), S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5), andS(O)₂NR^(c5)R^(d5); R^(c2) and R^(d2) are independently selected from H,C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, and heterocycloalkylalkyl, wherein said C₁₋₁₀ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl,cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted withOH, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or R^(c2)and R^(d2) together with the N atom to which they are attached form a4-, 5-, 6- or 7-membered heterocycloalkyl group; R^(c3) and R^(d3) areindependently selected from H, C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl,wherein said C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionallysubstituted with OH, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl;or R^(c3) and R^(d3) together with the N atom to which they are attachedform a 4-, 5-, 6- or 7-membered heterocycloalkyl group; R^(c4) andR^(d4) are independently selected from H, C₁₋₁₀ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, andheterocycloalkylalkyl, wherein said C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl isoptionally substituted with OH, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl orheterocycloalkyl; or R^(c4) and R^(d4) together with the N atom to whichthey are attached form a 4-, 5-, 6- or 7-membered heterocycloalkylgroup; R^(c5) and R^(d5) are independently selected from H, C₁₋₁₀ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl,cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, and heterocycloalkylalkyl, wherein said C₁₋₁₀ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl,cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted withOH, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or R^(c5)and R^(d5) together with the N atom to which they are attached form a4-, 5-, 6- or 7-membered heterocycloalkyl group; and R^(c6) and R^(d6)are independently selected from H, C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl,wherein said C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionallysubstituted with OH, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl;or R^(c6) and R^(d6) together with the N atom to which they are attachedform a 4-, 5-, 6- or 7-membered heterocycloalkyl group; and m, p, q, andr are independently selected from 0 and 1, with the provisos: (a) when X

Y is CR^(4a)R^(5a)—CR^(4b)R^(5b), then R² is other than halo, C₁₋₃haloalkyl, Z or SR^(A); (b) when X

Y is CR^(3a)═N, then R² is other than Z; (c) when X

Y is N═CR^(3b) and R^(3b) is H or unsubstituted aryl, then R² is otherthan unsubstituted aryl; (d) when X

Y is N═N, then R² is other than aryl; and (e) when X

Y is CR^(3a)═CR^(3b), then -L-R1 is other than methyl.
 2. The compoundof claim 1, or pharmaceutically acceptable salt thereof, wherein X is N.3. The compound of claim 1, or pharmaceutically acceptable salt thereof,wherein X is CH.
 4. The compound of claim 1, or pharmaceuticallyacceptable salt thereof, wherein Y is CR^(3b).
 5. The compound of claim1, or pharmaceutically acceptable salt thereof, wherein Y is CH.
 6. Thecompound of claim 1, or pharmaceutically acceptable salt thereof,wherein Y is C-Me.
 7. (canceled)
 8. The compound of claim 1, orpharmaceutically acceptable salt thereof, wherein R^(3a) and R^(3b) areindependently selected from H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, Cy¹, OR^(a), SR^(a),S(O)R^(b), S(O)₂R^(b), and NR^(c)R^(d), wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl are optionally substituted with 1, 2, or 3substitutents independently selected from Cy¹, CN, NO₂, halo, OR^(a),SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d),NR^(c)C(O)OR^(a), S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b),NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d).
 9. The compound of claim 1, orpharmaceutically acceptable salt thereof, wherein R^(3a) and R^(3b) areindependently selected from H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, Cy¹, OR^(a), SR^(a), andNR^(c)R^(d), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl areoptionally substituted with 1, 2, or 3 substitutents independentlyselected from Cy¹, CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d),C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a), S(O)R^(b), S(O)NR^(c)R^(d),S(O)₂R^(b), NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d).
 10. The compound ofclaim 1, or pharmaceutically acceptable salt thereof, wherein R^(3a) andR^(3b) are independently selected from H, halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, Cy¹, OR^(a),SR^(a), and NR^(c)R^(d), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl are optionally substituted with 1, 2, or 3 substitutentsindependently selected from Cy¹, C(O)NR^(c)R^(d), C(O)OR^(a), andNR^(c)C(O)R^(b).
 11. The compound of claim 1, or pharmaceuticallyacceptable salt thereof, wherein R^(3a) and R^(3b) are independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, Cy¹, halo, OR^(a), SR^(a),S(O)R^(b), S(O)₂R^(b), and NR^(c)R^(d), wherein said C₁₋₆ alkyl isoptionally substituted with 1, 2, or 3 substitutents independentlyselected from Cy¹, C(O)NR^(c)R^(d), C(O)OR^(a), halo, OR^(a),NR^(c)R^(d), NR^(c)C(O)NR^(c)R^(d), and NR^(c)C(O)R^(b).
 12. Thecompound of claim 1, or pharmaceutically acceptable salt thereof,wherein: at least one of R^(3a) and R^(3b) is selected from Cy¹; Cy¹ isselected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, eachoptionally substituted with 1, 2, 3, 4 or 5 substituents selected fromhalo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, OR^(a4),SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), and Cy³, whereinsaid C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl are optionallysubstituted with 1, 2, or 3 substituents independently selected fromhalo, OR^(a4) and Cy³; and Cy³ is selected from aryl, heteroaryl,cycloalkyl, and heterocycloalkyl, each optionally substituted with 1, 2,3, 4 or 5 substituents selected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, C₁₋₄ haloalkyl, aryl, heteroaryl, CN, NO₂, NR^(c6)R^(d6),OR^(a6), and SR^(a6).
 13. The compound of claim 1, or pharmaceuticallyacceptable salt thereof, wherein at least one of R^(3a) and R^(3b) isselected from C₁₋₆ alkyl and C₁₋₆ haloalkyl, wherein said C₁₋₆ alkyl isoptionally substituted with 1, 2, or 3 substitutents independentlyselected from C(O)NR^(c)R^(d), C(O)OR^(a), NR^(c)R^(d),NR^(c)C(O)NR^(c)R^(d), and NR^(c)C(O)R^(b).
 14. The compound of claim 1,or pharmaceutically acceptable salt thereof, wherein: at least one ofR^(3a) and R^(3b) is selected from C₁₋₃ alkyl, wherein said C₁₋₃ alkylis substituted with Cy¹ and optionally substituted with 1 or 2substitutents independently selected from halo, OR^(a), and SR^(a); Cy¹is selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl,each optionally substituted with 1, 2, 3, 4 or 5 substituents selectedfrom halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, CN,NO₂, OR^(a4), SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4),OC(O)R^(b4), OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4),S(O)₂NR^(c4)R^(d4), and Cy³, wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, andC₂₋₄ alkynyl are optionally substituted with 1, 2, or 3 substituentsindependently selected from OR^(a4) and Cy³; and Cy³ is selected fromaryl, heteroaryl, cycloalkyl, and heterocycloalkyl, each optionallysubstituted with 1, 2, 3, 4 or 5 substituents selected from halo, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, aryl, heteroaryl,cycloalkyl, heterocycloalkyl, CN, NO₂, OR^(a6), SR^(a6), C(O)R^(b6),C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6), OC(O)NR^(c6)R^(d6),NR^(c6)R^(d6), NR^(c6)C(O)R^(b6), NR^(c6)C(O)OR^(a6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), and S(O)₂NR^(c6)R^(d6).
 15. The compoundof claim 1, or pharmaceutically acceptable salt thereof, wherein: atleast one of R^(3a) and R^(3b) is selected from C₁₋₃ alkyl, wherein saidC₁₋₃ alkyl is substituted with Cy¹ and optionally substituted with 1 or2 substitutents independently selected from halo, OR^(a), and SR^(a);Cy¹ is selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl,each optionally substituted with 1, 2, 3, 4 or 5 substituents selectedfrom halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, CN,NO₂, OR^(a4), SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), andCy³, wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl areoptionally substituted with 1, 2, or 3 substituents independentlyselected from OR^(a4) and Cy³; and Cy³ is selected from aryl,heteroaryl, cycloalkyl, and heterocycloalkyl, each optionallysubstituted with 1, 2, 3, 4 or 5 substituents selected from halo, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, aryl, heteroaryl, CN,NO₂, NR^(c6)R^(d6), OR^(a6), and SR^(a6).
 16. The compound of claim 1,or pharmaceutically acceptable salt thereof, wherein: at least one ofR^(3a) and R^(3b) is independently selected from C₁₋₃ alkyl, whereinsaid C₁₋₃ alkyl is substituted with Cy¹ and optionally substituted with1 or 2 substitutents independently selected from halo, OR^(a), andSR^(a); Cy¹ is selected from aryl, heteroaryl, cycloalkyl, andheterocycloalkyl, each substituted with 1 or 2 R⁷ and optionallysubstituted by 1, 2, or 3 R⁸; R⁷ is, at each occurrence, independentlyselected from Cy³ and C₁₋₄ alkyl, wherein said C₁₋₄ alkyl is substitutedwith 1 or 2 Cy³ and optionally substituted with 1 or 2 substituentsindependently selected from halo and OR^(a4); R⁸ is, at each occurrence,independently selected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ haloalkyl, CN, NO₂, OR^(a4), SR^(a4), C(O)R^(b4),C(O)NR^(c4)R^(d4), and C(O)OR^(a4); and Cy³ is selected from aryl,heteroaryl, cycloalkyl, and heterocycloalkyl, each optionallysubstituted with 1, 2, 3, 4 or 5 substituents selected from halo, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, aryl, heteroaryl, CN,NO₂, NR^(c6)R^(d6), OR^(a6), and SR^(a6).
 17. The compound of claim 1,or pharmaceutically acceptable salt thereof, wherein R^(3a) and R^(3b)are independently selected from H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, and C₁₋₆ haloalkyl.
 18. The compound of claim 1, orpharmaceutically acceptable salt thereof, wherein R^(3a) and R^(3b) areindependently selected from aryl, heteroaryl, cycloalkyl, andheterocycloalkyl.
 19. The compound of claim 1, or pharmaceuticallyacceptable salt thereof, wherein R^(3b) is heteroaryl optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom aryl, cycloalkyl, and heterocycloalkyl, each optionally substitutedwith 1, 2, 3, 4 or 5 substituents selected from halo, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, CN, NO₂, OR^(a6), and SR^(a6).
 20. The compound ofclaim 1, or pharmaceutically acceptable salt thereof, wherein R^(3b) isthiazolyl that is optionally substituted with phenyl, wherein saidphenyl is optionally substituted with 1, 2, 3, 4, or 5 substituentsindependently selected from OH and halo.
 21. The compound of claim 1, orpharmaceutically acceptable salt thereof, wherein Cy¹ is selected fromaryl, heteroaryl, cycloalkyl, and heterocycloalkyl, each optionallysubstituted with 1, 2, 3, 4 or 5 substituents selected from halo, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, CN, NO₂, OR^(a4),SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4),OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4),S(O)₂NR^(c4)R^(d4), and Cy³, wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, andC₂₋₄ alkynyl are optionally substituted with 1, 2, or 3 substituentsindependently selected from OR^(a4) and Cy³.
 22. The compound of claim1, or pharmaceutically acceptable salt thereof, wherein m and q are 0.23. The compound of claim 1, or pharmaceutically acceptable saltthereof, wherein R¹ is H or C₁₋₁₀ alkyl.
 24. The compound of claim 1, orpharmaceutically acceptable salt thereof, wherein -L-R¹ is C₁₋₁₀ alkyl.25. The compound of claim 1, or pharmaceutically acceptable saltthereof, wherein -L-R¹ is C₄₋₇ alkyl optionally substituted with 1, 2,3, 4 or 5 substitutents each independent selected from halo, OH, and CN.26. The compound of claim 1, or pharmaceutically acceptable saltthereof, wherein -L-R¹ is butyl or pentyl.
 27. The compound of claim 1,or pharmaceutically acceptable salt thereof, wherein R² is halo, cyano,C₁ haloalkyl, Z, SR^(A), or a moiety having the formula:


28. The compound of claim 1, or pharmaceutically acceptable saltthereof, wherein R² is halo, cyano, C₁ haloalkyl, Z, or, SR^(A).
 29. Thecompound of claim 1, or pharmaceutically acceptable salt thereof,wherein R² is halo, cyano, or C₁ haloalkyl.
 30. The compound of claim 1,or pharmaceutically acceptable salt thereof, wherein R² is halo or C₁haloalkyl.
 31. The compound of claim 1, or pharmaceutically acceptablesalt thereof, wherein R² is Cl, Br, or CF₃.
 32. The compound of claim 1,or pharmaceutically acceptable salt thereof, wherein R² is Cl or Br. 33.The compound of claim 1, or pharmaceutically acceptable salt thereof,wherein R² is Br.
 34. The compound of claim 1, or pharmaceuticallyacceptable salt thereof, wherein R² a moiety having the formula:


35. The compound of claim 1, or pharmaceutically acceptable saltthereof, wherein R² is S-Me.
 36. The compound of claim 1, orpharmaceutically acceptable salt thereof, wherein R² is selected fromaryl, heteroaryl, cycloalkyl, and heterocycloalkyl, each optionallysubstituted with 1, 2, 3, 4 or 5 substituents selected from halo, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, and OR^(a4). 37-59.(canceled)
 60. A composition comprising a compound of claim 1, orpharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable carrier.
 61. A composition comprising acompound of claim 31, or pharmaceutically acceptable salt thereof, andat least one pharmaceutically acceptable carrier.
 62. A compositioncomprising a compound of claim 32, or pharmaceutically acceptable saltthereof, and at least one pharmaceutically acceptable carrier. 63-80.(canceled)